On April 1, 2019 Puma Biotechnology, Inc. (Nasdaq: PBYI) and Pierre Fabre reported that they have entered into an exclusive license agreement under which Pierre Fabre will develop and commercialize NERLYNX (neratinib) within Europe and part of Africa (Press release, Puma Biotechnology, APR 1, 2019, View Source [SID1234534843]). In September 2018 the European Commission granted marketing authorization for NERLYNX (neratinib) for the extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab-based therapy.

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Pierre Fabre will have exclusive commercialization rights for NERLYNX in European countries excluding Russia and Ukraine, along with countries in North Africa and francophone countries of West Africa. Pierre Fabre will also be responsible for conducting additional clinical studies and leading regulatory activities in connection with the European Medicines Agency (EMA).

Under the terms of the agreement, Puma will receive an upfront payment of $60 million, as well as additional regulatory and commercial milestone payments totaling up to $345 million. In addition, Puma will receive significant double-digit royalties on NERLYNX sales throughout the territory covered by the license agreement between Puma and Pierre Fabre.

"Puma is committed to providing access to NERLYNX to patients around the world and soon physicians and patients in Europe will have commercial availability of NERLYNX," stated Alan H. Auerbach, Chief Executive Officer and President of Puma. "Pierre Fabre has a robust commercial and medical oncology infrastructure that we hope will lead to rapid commercial access to NERLYNX."

"We are thrilled to provide this new therapy to patients with HER2-positive breast cancer throughout Europe," said Frederic Duchesne, Chief Executive Officer, Pierre Fabre Pharmaceuticals. "Pierre Fabre has developed a strong expertise and presence in breast cancer treatment and the addition of NERLYNX to our historical oncology portfolio will allow us to strengthen our commercial presence. We anticipate providing access to NERLYNX to patients throughout Europe in 2019 and 2020, starting with Germany."

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

Important EU NERLYNX (neratinib) Safety Information

All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in the randomized Phase 3 clinical trial (n=2840). The most common adverse reactions of any grade were diarrhoea (93.6%), nausea (42.5%), fatigue (27.3%), vomiting (26.8%), abdominal pain (22.7%), rash (15.4%), decreased appetite (13.7%), abdominal pain upper (13.2%), stomatitis (11.2%), and muscle spasms (10.0%).

The most common Grade 3-4 adverse reactions were diarrhoea (Grade 3, 36.9% and Grade 4, 0.2%) and vomiting (Grade 3, 3.4% and Grade 4, 0.1%).

Adverse reactions reported as serious included diarrhoea (1.9%), vomiting (1.3%), dehydration (1.1%), nausea (0.5%), alanine aminotransferase increased (0.4%), aspartate aminotransferase increased (0.4%), abdominal pain (0.3%), fatigue (0.3%) and decreased appetite (0.2%).

For full European prescribing information, please refer to the NERLYNX (neratinib) Summary of Product Characteristics on the European Medicines Agency website (View Source).

Important Safety Information Regarding NERLYNX (neratinib) U.S. Indication

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX inpatients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. When patients require gastric acid reducing agents, use an H2-receptor antagonist or antacid. Separate NERLYNX by at least 3 hours with antacids. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.

On April 1, 2019 Peloton Therapeutics, Inc., a clinical-stage biopharmaceutical company advancing first-in-class oral medicines for cancer and other serious conditions, reported the presentation of data from the Phase 2 portion of the company’s Phase 1/2 clinical trial of its lead drug candidate, PT2977, at the Fourteenth European International Kidney Cancer Symposium in Dubrovnik, Croatia (Press release, Peloton Therapeutics, APR 1, 2019, View Source [SID1234534842]). In the Phase 2 portion of the trial, highlighted in an oral presentation and poster session at the symposium, PT2977 showed encouraging anti-tumor activity with a favorable safety profile in patients with previously-treated advanced renal cell carcinoma (RCC).

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The presentation titled, "A First-in-Human Phase 1/2 Trial of the Oral HIF-2α Inhibitor PT2977 in Patients with Advanced RCC," was delivered by lead author Toni K. Choueiri, M.D., Director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School.

PT2977 is an oral, small molecule inhibitor of hypoxia-inducible factor (HIF)-2α, a transcription factor that is the key oncogenic driver in RCC. Inhibiting HIF-2α can impact multiple pathways that contribute to RCC progression.

The Phase 1/2 study evaluated the safety and efficacy of PT2977. The Phase 1 portion included a once daily administration schedule dose escalation cohort of 37 patients with advanced solid tumors. Based on the results of this cohort, 120 mg once daily was selected as the recommended Phase 2 dose (RP2D). In the Phase 2 portion, 52 patients with advanced clear-cell RCC who had received at least one prior therapy received PT2977 at the RP2D. The data presented included all 52 patients from the Phase 2 portion and three RCC patients from the Phase 1 portion treated at the RP2D, for a total of 55 patients. The data cut-off date for the presentation was January 1, 2019.

Among the 55 patients who were treated at the RP2D, 12 patients (22%) had a confirmed partial response. Median progression free survival (PFS) was not yet reached in the study with a median follow-up of 9 months, and 36% of patients remained on study at the time of the data cut-off.

PT2977 was well tolerated. The most common adverse event was anemia, which was anticipated given regulation of erythropoietin (EPO) by HIF-2α. Two patients discontinued treatment for drug-related adverse events and three other patients required dose reductions for drug-related adverse events.

"The data from this trial indicate that HIF-2α inhibition has the potential to become a promising new treatment option for patients with renal cancer," said Dr. Choueiri. "The data show that PT2977 can provide clinically meaningful responses in heavily pre-treated patients with a favorable safety and tolerability profile."

"We are delighted with these results," said John A. Josey, Ph.D., Peloton’s Chief Executive Officer. "The data presented today pave the way for a planned monotherapy Phase 3 trial that will further explore this exciting new mechanism of action in patients with advanced kidney cancer."

Further information on the clinical trial of PT2977 can be found on clinicaltrials.gov (Study identifier: NCT02974738). The poster and presentation slides are available online at: View Source

About PT2977

PT2977 is a once-daily, oral inhibitor of hypoxia-inducible factor-2α (HIF-2α). PT2977 has demonstrated anti-tumor activity with a favorable safety profile in an early-stage clinical study in patients with solid tumors. Peloton is also currently evaluating PT2977 in an international Phase 2 trial in von Hippel-Lindau (VHL) disease-associated RCC.

On April 1, 2019 Oncorus, Inc., an oncolytic virus therapeutics company focused on driving innovation to transform outcomes for cancer patients, reported preclinical data yesterday supporting the clinical advancement of its lead oncolytic virus candidate, ONCR-177, during an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Oncorus, APR 1, 2019, View Source [SID1234534841]). The data demonstrated that intra-tumoral administration of ONCR-177 resulted in high partial and complete response rates on both injected and non-injected tumors in preclinical models of several tumor types, including immune-inert, or cold, tumors. Responses were durable, resulting in an extension of survival and the establishment of protective immunity against tumor re-challenge.

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ONCR-177, a locally administered oncolytic virus therapy for the treatment of multiple solid tumor indications, is built on Oncorus’ proprietary, next-generation oncolytic herpes simplex virus (HSV) platform. ONCR-177 is armed with five transgenes, IL-12, CCL4, FLT3L, and CTLA-4 and PD-1 antagonists – representing the largest payload in the oncolytic virus therapy class – for potent stimulation of anti-tumor immunity. The therapy also employs an innovative microRNA (or miR)-attenuation strategy to enable selective viral replication in tumor cells, while preventing replication in healthy tissues.

"We are excited to share these important data driving the clinical advancement of ONCR-177," said Theodore (Ted) Ashburn, M.D., Ph.D., President and Chief Executive Officer of Oncorus. "We are highly encouraged by the responses we’ve seen to treatment with ONCR-177 in multiple preclinical models as a result of the proprietary potency and safety innovations we have engineered. Our team continues to make remarkable progress on several fronts as we advance our best-in-class portfolio of oncolytic virus therapies for both local and systemic administration toward the clinic, with the goal of transforming outcomes for cancer patients."

Oncorus plans to file an investigational new drug application (IND) for ONCR-177 in 2019. In addition to its oncolytic HSV platform, Oncorus is also developing a novel synthetic oncolytic virus platform to enable the development of oncolytic virus therapies for repeated, systemic administration for uninjectable tumors, such as those of the lung.

About the Preclinical Findings

Intra-tumoral administration of the mouse surrogate of ONCR-177 in the oncolytic HSV-sensitive A20 BALB/c lymphoma bilateral tumor model resulted in response rates (partial and complete tumor regressions) of 100% and 80%, respectively, on the injected and uninjected tumor. mONCR-177 was also highly efficacious in the B16F10-nectin 1 melanoma model, an oncolytic HSV-resistant C57BL/6 based tumor model engineered to be permissive to oncolytic HSV by introduction of nectin-1, and in two colon carcinoma models CT26 and MC38.

mONCR-177 treatment resulted in increased numbers of activated NK cells, CD8+ and CD4+ effector T cells, and classical dendritic cells. The proportion of regulatory T cells, or Tregs, decreased, resulting in large increases CD8/Treg ratios. These changes in immune contexture occurred in both injected and uninjected tumors. They were more pronounced with mONCR-177 treatment compared to the base vector without payloads, indicating that the observed abscopal effects were due to mONCR-177’s elicitation of systemic anti-tumor immunity mediated in part by its payload of multiple transgenes.

"Due to their ability to kill cancer cells while eliciting a potent systemic antitumor immune response, ONCR-177 represents a potentially transformational treatment modality for cancer, as a monotherapy and in combination with checkpoint inhibitors," said Christophe Quéva, Ph.D., Oncorus’ Chief Scientific Officer. "At Oncorus, we have made important strides to overcome the ‘potency versus safety’ tradeoff that has historically held back this class of therapeutics, and we look forward to moving ONCR-177 into the clinic."

Oncorus has three additional poster presentations at the AACR (Free AACR Whitepaper) meeting showcasing the company’s proprietary potency and safety innovations for both its oncolytic HSV and synthetic oncolytic virus platforms, including:

Abstract #: 1455
Title: Design of ONCR-177 base vector, a next generation oncolytic herpes simplex virus type-1, optimized for robust oncolysis, transgene expression and tumor-selective replication
Session: PO.IM02.08 — Cancer Vaccines and Intra-tumoral Immunomodulation
Date and Time: Monday, April 1, 2019 / 8:00 am – 12:00 pm EDT
Location: Poster Section 22
Abstract Link: View Source!/6812/presentation/2749

Abstract #: 1452
Title: Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response
Session: PO.IM02.08 — Cancer Vaccines and Intra-tumoral Immunomodulation
Date and Time: Monday, April 1, 2019 / 8:00 am – 12:00 pm EDT
Location: Poster Section 22
Abstract Link: View Source!/6812/presentation/2746

Abstract #: 4773
Title: Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression
Session: PO.ET08.01 — Gene- and Vector-based Therapy
Date and Time: Wednesday, April 3, 2019 / 8:00 am – 12:00 pm EDT
Location: Poster Section 12
Abstract Link: View Source!/6812/presentation/1354

On April 1, 2019 SpringWorks Therapeutics, Inc. (the "Company"), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported the closing of a $125 million Series B preferred stock financing led by Perceptive Advisors (Press release, SpringWorks Therapeutics, APR 1, 2019, View Source [SID1234534840]). New investors participating in this financing include Boxer Capital of Tavistock Group, HBM Healthcare Investments, BVF Partners, Surveyor Capital (a Citadel company), Samsara BioCapital, ArrowMark Partners, GlaxoSmithKline (NYSE: GSK), and Laurion Capital Management, as well as several other long-term institutional investors. All of the Company’s existing investors – OrbiMed, Bain Capital, Pfizer (NYSE: PFE), via Pfizer Ventures, and LifeArc – also participated in the offering.

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Proceeds from the financing will be used to advance the Company’s two late-stage rare disease oncology programs towards potential regulatory approval and commercialization: nirogacestat, a gamma secretase inhibitor for the treatment of desmoid tumors, and PD-0325901, a MEK inhibitor for the treatment of neurofibromatosis type 1-associated plexiform neurofibromas. The proceeds will also support the continued expansion of the Company’s emerging targeted oncology programs, as well as future in-licensing opportunities and clinical collaborations in rare diseases and cancer.

"This financing from a committed, knowledgeable and distinguished investor syndicate, which includes new and existing investors as well as key industry partners, underscores the progress we’ve made to advance our late-stage clinical programs towards pivotal studies, execute on our initial business development strategy, and build upon our leading drug development operations," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We are well positioned to continue to execute on our strategy to build a leading rare disease and targeted oncology company that brings promising science to underserved patient communities."

"We are excited to partner with SpringWorks Therapeutics as they build a differentiated rare disease and targeted oncology company, and we look forward to supporting the team as they work towards achieving product approvals over the coming years," said Adam Stone, Chief Investment Officer of Perceptive Advisors, LLC.

On April 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported promising data from the Company’s growing bispecific and TAM (Tyro3, Axl, MerTK) receptor programs during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 1, 2019, View Source [SID1234534839]).

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"Our research and discovery efforts have yielded multiple promising candidates that address important needs in cancer immunotherapy and complement our pipeline," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "CDX-527 joins two powerful pathways in the immune system, PD-1 blockade and CD27 costimulation. The data we presented at AACR (Free AACR Whitepaper) demonstrate that this bispecific antibody candidate has greater activity than the combination of the two individual antibodies and support advancing the program into IND-enabling studies. In addition, we also presented data on our lead candidate antibodies targeting the TAM receptors, which act as checkpoints on myeloid cells. We have uncovered a unique mechanism for antibody-mediated activation of dendritic cells and macrophages and demonstrated that a surrogate MerTK mAb promotes anti-tumor immunity alone and enhances the activity of PD-1 blockade. We look forward to continuing to progress both CDX-527 and our TAM program over the course of the year," concluded Keler.

Presentation Highlights:

Poster #2392: CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1 (Vitale, et. al)

The use of bispecific antibodies provides opportunities to engage two independent pathways involved in controlling immune responses to tumors. Preclinical and clinical studies support the safety and benefit of combining PD-1 blockade with a CD27 agonist.
The bispecific CDX-527 combines a novel and potent PD-L1 antibody for blocking the PD-1 checkpoint pathway with the binding domains of a CD27 agonist antibody for CD27-mediated costimulation of T cells.
CDX-527 demonstrated potent inhibition of PD-1 signaling and T cell activation using in vitro models with reporter cell lines and human primary cell cultures.
Anti-tumor activity was tested with a surrogate bispecific molecule that binds mouse PD-L1 and human CD27 in human CD27-expressing transgenic mice. The bispecific demonstrated potent anti-tumor activity in a BCL1 lymphoma model and was significantly more effective than the combination of the CD27 and PD-L1 monoclonal antibodies (mAbs).
A pilot study in non-human primates suggests that CDX-527 demonstrates good pharmacokinetic properties and no toxicities were observed.
Based on the promising data observed to date and the PK/PD profiles, Celldex has initiated manufacturing activities and investigational new drug (IND) enabling studies to support clinical studies of CDX-527.
Poster #1555: Monoclonal antibodies targeting the TAM family of receptor tyrosine kinases (Alvarado, et al)

TAM receptors (Tyro3, Axl, MerTK) are receptor tyrosine kinases (RTKs) expressed in innate immune cells. These receptors have been gaining importance in the immunotherapy field due to their role as checkpoint molecules on macrophages, dendritic cells, and other immune cells, where they can negatively regulate anti-tumor immunity.
Celldex presented data showing that lead candidate mAbs targeting MerTK, Axl or Tyro-3 activate myeloid cells, including monocytes, macrophages and dendritic cells, enhancing pro-inflammatory cytokine release, increasing expression of costimulatory molecules and enhancing T cell activation in mixed lymphocyte reaction (MLR) assays.
Celldex demonstrated that the potent activity of the TAM-specific antibodies are dependent on a unique coupling of the TAM receptors with Fc receptors.
Celldex’s most advanced program targets MerTK, where the Company has demonstrated that antibody targeting of MerTK in mice elicits an inflammatory cytokine response similar to that observed in the human cells and in MerTK deficient mice and has anti-tumor activity when dosed alone or in combination with a PD-1 inhibitor in a colon cancer model.
These data support development of anti-TAM mAbs as therapies to activate innate immune responses with a potential for systemic dosing. The Company intends to advance potential candidates into development activities this year.