On October 24, 2019 Replimune Group Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported that the company has enrolled the first patient in its Phase 1 clinical trial of RP2 (Press release, Replimune, OCT 24, 2019, View Source [SID1234542485]). RP2 expresses a genetically encoded anti-CTLA-4 antibody-like molecule, in addition to GALV-GP-R- and GM-CSF, both of which are expressed in Replimune’s first product candidate, RP1. This is intended to block the inhibition of the initiation of immune responses caused by CTLA-4.

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"We are excited to be advancing RP2, our second novel Immulytic product candidate, into clinical studies," said Robert Coffin, Ph.D., co-founder, President and CEO of Replimune. "CTLA-4 inhibition is an established mechanism of action for cancer treatment, including proven synergy with anti-PD1 therapy. By combining the expression of anti-CTLA-4 with oncolytic tumor destruction and antigen release directly in the tumor and draining lymph nodes, we believe that the efficacy of CTLA-4 inhibition can be enhanced with RP2, while reducing toxicity as compared to systemic administration."

The Phase 1 clinical trial will study RP2 as a single agent and in combination with Opdivo (nivolumab) in patients with advanced solid tumors. The Phase 1 clinical trial is designed to assess the safety, tolerability and to determine the optimal dose of RP2 alone and in combination with anti-PD1 therapy and is being conducted as a collaboration with Bristol-Myers Squibb Company (BMS). BMS has granted Replimune a nonexclusive, non-transferable, royalty-free license to, and will supply at no cost, Opdivo, for use in combination with RP2. BMS has no further development-related obligations under this collaboration.

About RP2

RP2 is Replimune’s second Immulytic product candidate and like RP1, is based on a proprietary new strain of herpes simplex virus which expresses GM-CSF and the fusogenic protein GALV-GP R-. In addition to the properties of RP1, RP2 expresses an anti-CTLA-4 antibody-like protein in order to block the inhibition of the immune response otherwise caused by CTLA-4. In preclinical studies comparing RP1 to RP2 to determine the effect of expressing anti-CTLA-4, RP2 demonstrated enhanced efficacy both alone and in combination with anti-PD1 therapy both in tumors which were injected with RP1 or RP2 and in tumors which were left uninjected

On October 24, 2019 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing a new class of potent and selective precision oncology medicines for the treatment of patients with a wide range of solid tumor malignancies, reported the publication of several preclinical studies evaluating PEN-221 as a novel therapeutic for the treatment of small cell lung cancer (SCLC) (Press release, Tarveda Therapeutics, OCT 24, 2019, View Source [SID1234542504]). The publication, "Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer," was published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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PEN-221 is a miniature drug conjugate comprising a peptide that is highly selective for somatostatin receptor 2 (SSTR2) conjugated to the potent tubulin inhibitor payload, DM1, via a tuned cleavable linker. SSTR2 is overexpressed on the surface of cancer cells in patients with a range of solid tumors including SCLC and neuroendocrine cancers.

"These studies demonstrate that the unique attributes of our PEN-221 miniature drug conjugate allow for deep tumor penetration, while limiting plasma and normal tissue exposure. We engineered PEN-221 to have these attributes in order to enable long-term dosing of our conjugate and cause durable tumor control, as was demonstrated in our published studies," said Mark Bilodeau, Chief Scientific Officer of Tarveda.

The publication shows a series of mouse xenograft efficacy studies where PEN‑221 treatment resulted in significant antitumor activity, including enduring and complete regressions in multiple SSTR2 positive SCLC models. PEN-221 treatment of SSTR2 positive SCLC xenograft tumors also showed potent and durable tumor inhibition superior to the currently used standard of care treatment for SCLC.

Additional studies elucidated how PEN-221 causes cell cycle arrest and tumor cell death. Mouse xenograft models demonstrated how the unique miniature conjugate structure of PEN-221 allows deep penetration into the tumor causing mitotic arrest while rapidly and durably delivering DM1, the toxic payload, into the tumor. The relatively short plasma exposure of PEN-221 and its DM1 payload limits damage to normal tissue, and PEN-221 was well tolerated in our Phase 1 study, which was presented at ASCO (Free ASCO Whitepaper) 2018.

Together, these results show that the unique attributes of PEN-221, including deep tumor penetration, rapid delivery of its toxic payload and limited exposure to normal cells may potentially offer distinct advantages in treating SCLC and GI neuroendocrine cancers compared to current therapeutic options.

"Based on the encouraging results from these studies, we initiated a Phase 1/2a clinical trial of PEN-221 in patients with a focus on both gastrointestinal neuroendocrine tumors and small cell lung cancer," said Jeffrey D. Bloss, Chief Medical Officer of Tarveda. "The Phase 1 portion of the study showed that PEN-221 was well tolerated with evidence of antitumor activity seen in multiple patients. We were encouraged by these results and initiated the Phase 2a portion of the study, which is currently enrolling patients with results expected in 2020."

About Small Cell Lung Cancer
Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancers in the U.S. with few new recent therapeutic options available despite over 60 agents that have been investigated in clinical trials. SCLC is an aggressive disease that spreads quickly and most patients with SCLC experience rapid disease progression before symptoms appear, resulting in about 7% survival at five years. In addition to the lack of early symptoms, the lack of early detection reduces the chances for an optimal therapeutic response.

About PEN-221
PEN-221 is a miniature drug conjugate consisting of a peptide ligand, that is highly selective in targeting SSTR2, joined through a cleavable linker to the potent cytotoxic payload DM1. SSTR2 is overexpressed on the cell surface of a range of solid tumors including neuroendocrine tumors and small cell lung cancer. In non-clinical experiments, PEN-221 binds with high affinity and selectivity to SSTR2. On binding, PEN-221 triggers SSTR2 internalization resulting in the accumulation of the DM1 payload in tumor cells followed by cell cycle arrest and apoptosis.

PEN-221 is being evaluated in Phase 2a expansion cohorts currently enrolling patients with midgut neuroendocrine tumors and small cell lung cancer (ClinicalTrials.gov Identifier: NCT02936323).

On October 24, 2019 Cambrex Corporation (NYSE: CBM), the leading small molecule company providing drug substance, drug product and analytical services across the entire drug lifecycle, reported that in connection with the debt portion of the financing for the pending acquisition by an affiliate of the Permira Funds, they are making the following third quarter 2019 preliminary unaudited financial information available to prospective lenders (Press release, Cambrex, OCT 24, 2019, View Source [SID1234542469]).

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The financial results presented above are unaudited and preliminary estimates that (i) represent the most current information available to management as of the date of this press release, (ii) are subject to completion of financial closing and procedures that could result in significant changes to the estimated amounts, and (iii) do not present all information necessary for an understanding of Cambrex’s financial condition as of, and its results of operations for the quarter ended, September 30, 2019. Accordingly, undue reliance should not be placed on such preliminary estimates.

Use of Non-GAAP Financial Measures
EBITDA and Adjusted EBITDA are non-GAAP financial measures ("non-GAAP financial measures"). Other companies may have different definitions of these non-GAAP financial measures, and as a result they may not be comparable with non-GAAP financial measures provided by other companies.

EBITDA and Adjusted EBITDA should not be considered alternatives to measurements required by U.S. GAAP, such as Operating profit, and should not be considered a measure of Cambrex’s liquidity.

Cambrex uses these non-GAAP financial measures, among several other metrics, to assess and analyze its operational results and trends. Cambrex also believes these measures are useful to investors because they are common operating performance metrics as well as metrics routinely used to assess potential enterprise value. Cambrex has provided a reconciliation of U.S. GAAP amounts to non-GAAP amounts within this press release.

On October 24, 2019 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported that updated clinical data from its ongoing Phase 2 trial evaluating SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacitidine, continue to demonstrate high complete response rates, rapid onset of action and a favorable tolerability profile in a genomically defined subset of newly diagnosed acute myeloid leukemia (AML) patients who are not suitable candidates for standard intensive chemotherapy (Press release, Syros Pharmaceuticals, OCT 24, 2019, View Source [SID1234542486]). These data are being presented at the European School of Haematology (ESH) 5th International Conference Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment in Estoril, Portugal.

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"I am very encouraged by these data. AML patients continue to need new treatment options, despite recent advances in the field, that are well-tolerated and can be used in combination to extend survival and improve quality of life," said Stéphane de Botton, M.D., Head of Acute Myeloid Malignancies at Institut Gustave Roussy and a clinical investigator in the Phase 2 trial of SY-1425. "These data show that SY-1425, a targeted therapy, in combination with azacitidine is highly active in a subset of patients that can be readily identified and that the combination is generally well-tolerated even in very sick AML patients. I believe SY-1425 is a promising combination agent with the potential to provide a meaningful benefit for a subset of AML patients, and I look forward to its continued development."

"These data mark an important milestone in the development of SY-1425," said David A. Roth, M.D., Chief Medical Officer of Syros. "SY-1425 in combination with azacitidine continues to demonstrate high complete response rates, rapid onset of action and a favorable tolerability profile in RARA-positive AML patients. As we study the combination in more patients, we are also seeing a high rate of transfusion independence and early evidence of durable responses. We are gratified to see our discovery of this novel patient subset, as defined by our RARA biomarker, translating into clinical benefit. These results demonstrate the power of our gene control platform to identify which genes to modulate in which patients to maximize the chances of providing them with a profound benefit. We look forward to continuing to evaluate SY-1425 in our ongoing study and to reporting potential proof-of-concept data next year in RARA-positive relapsed or refractory AML patients."

Updated Clinical Data on SY-1425 in Combination with Azacitidine in Newly Diagnosed, Unfit AML Patients

Syros presented updated data from its Phase 2 trial of SY-1425 in combination with azacitidine, a standard-of-care hypomethylating agent, in newly diagnosed unfit AML patients. The trial evaluated the safety and efficacy of the combination in patients with either the RARA or IRF8 biomarker, as well as in patients without the biomarkers. All patients were treated with azacitidine administered at standard daily doses of 75 mg/m2 intravenously or subcutaneously for seven days, followed by SY-1425 administered at 6 mg/m2/day orally, divided in two doses, for the remainder of each 28-day cycle.

As of Aug. 22, 2019, 40 newly diagnosed unfit AML patients had been enrolled in the trial and were eligible for the safety analysis. The median age of patients enrolled in the study was 76. Of the 17 biomarker-positive patients evaluable for response, 13 were RARA-positive and four were IRF8-positive. Enrollment in the newly diagnosed unfit cohorts of the ongoing Phase 2 trial is nearly complete. Syros will continue to follow patients enrolled in the trial to further characterize the overall profile of the combination, including safety, efficacy and durability of response.

Clinical Activity Data

62% complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group, IWG, criteria), in RARA-positive patients.

54% CR rate in RARA-positive patients, consisting of seven CRs, including three molecular CRs and three cytogenetic CRs.

Most initial responses were seen at the first response assessment.

Duration of these responses in RARA-positive patients was up to 344 days, with three of the eight responding patients having responses lasting beyond seven months at the time of the data cutoff.

82% of RARA-positive patients achieved or maintained transfusion independence.

Responses were seen in RARA-positive patients across AML risk groups, including patients with mutations that are typically associated with poor outcomes.

In patients with only the IRF8-biomarker, the CR/CRi rate was 0%, supporting Syros’ decision to use RARA as the sole biomarker for patient selection in SY-1425 clinical trials going forward. Based on data from 112 newly diagnosed patients screened for its clinical trial, Syros believes that approximately 30% of newly diagnosed AML patients are RARA-positive.

In the 22 response-evaluable RARA-negative patients, the CR/CRi rate was 27%, which is consistent with the published response rates of 18-29% observed in newly diagnosed unfit AML patients treated with single-agent azacitidine.

Safety Data

SY-1425 in combination with azacitidine was generally well-tolerated with no evidence of increased toxicities beyond what is seen with either SY-1425 or azacitidine alone.

Rates of myelosuppression, including neutropenia, were comparable to reports of single-agent azacitidine in this AML population.

The majority of non-hematologic AEs were low grade.

Across all grades and causalities, the most commonly reported AEs were nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%) and peripheral edema (30%).

The most commonly reported Grade 3 or higher AEs (all causality) were thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%).

The poster presented at ESH is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

The ongoing Phase 2 trial is actively enrolling patients with relapsed or refractory AML patients who are positive for the RARA biomarker. Syros expects to report potential proof-of-concept from the cohort in relapsed or refractory AML patients in 2020. Additional details about the Phase 2 trial of SY-1425 can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

On October 24, 2019 Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for cancer, reported that the company will participate in the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) 2019 in Boston, October 27-30, including a poster presentation on October 27th (Press release, Personalis, OCT 24, 2019, View Source [SID1234542505]).

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The poster presentation, titled "A comprehensive, highly accurate genomics platform for precision immunotherapy: Simultaneously characterize tumors and the TME from a single FFPE sample," will describe the Personalis universal cancer immunogenomics platform, ImmunoID NeXT. The poster will provide an overview of how the platform can be used to explore critical immunotherapy-related biomarkers of resistance and response; utilizing analytics including: human leukocyte antigen (HLA) typing and HLA loss of heterozygosity (LOH), neoantigen prediction and load, immune repertoire characterization, oncoviral detection, immune cell deconvolution, as well as the evaluation of tumor mutational burden (TMB) and microsatellite instability (MSI) status.

ImmunoID NeXT is the first platform to enable comprehensive analysis of both a tumor and its immune microenvironment from a single sample. The platform can be used to investigate the key tumor- and immune-related areas of cancer biology, consolidating multiple oncology biomarker assays into one and maximizing the biological information that can be generated from a precious tumor specimen.

The presentation will be delivered by Robert Power, M.S., Product Manager.