On August 5, 2020 Sysmex Inostics, Inc., a global leader and pioneer in blood-based circulating tumor DNA (ctDNA) analysis for oncology, reported the publication of a clinical study evaluating the performance of plasma RAS mutation testing with OncoBEAM RAS CRC as compared to standard of care tissue-based RAS testing in the United Kingdom (UK) (Press release, Sysmex Inostics, AUG 5, 2020, View Source [SID1234568250]).

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OncoBEAM RAS CRC is a CE-IVD test that uses BEAMing technology, an enhanced digital PCR method optimized for high sensitivity blood-based mutation detection for metastatic colorectal cancer (mCRC) patients. This is the first study of its kind in the UK with confirmatory testing performed across laboratories certified to run the OnocBEAM RAS CRC test. Investigators also utilized the highly sensitive nature of OncoBEAM testing to also explore the clinical value of detecting changes in plasma RAS mutation status in patients treated with anti-EGFR antibody therapy.

The overall percent agreement between the OncoBEAM assay and tissue-based testing for RAS mutations was 86.0% (86/100), with a 100% reproducibility of test results between three labs located in the UK, Germany, and Japan. This demonstrates that blood-based testing with an appropriate and well validated assay can serve as an alternative to tissue-based testing and can improve access to precision medicine globally.

Colorectal cancer (CRC) continues to be one of the leading causes of cancer-related deaths globally. Anti-EGFR monoclonal antibodies have demonstrated significant improvements in survival of patients with wild-type RAS tumors mCRC. However, tissue-based biomarker testing has been shown to present several challenges, such as tumor molecular heterogeneity, poor tissue quality, and logistical issues, which can contribute to delays in treatment initiation. Importantly, as patients undergo treatment with targeted therapies, insight into changing tumor molecular dynamics would require repeat tissue biopsies, which is not practical in routine clinical management. Since mCRC patients already undergo regular blood draws throughout treatment; testing with the OncoBEAM RAS assay can deliver valuable insights into tumor response.

The ability to draw serial blood samples and perform OncoBEAM ctDNA longitudinal analyses of RAS mutant allelic fraction (MAF) variation before and during anti-EGFR therapy provides opportunities to identify emerging RAS mutant clones early during treatment. This minimally invasive approach provides better visualization of treatment responses and failures, enabling personalized therapy approaches for mCRC patients, with the goal of improving outcomes. The lead and senior authors of the study, Dr. Theodora Germetaki and Dr. Mark Saunders, Department of Medical/Clinical Oncology, The Christie Hospital, Manchester, UK conclude: "We showed that 20% of patients showed a change in their RAS mutational status during treatment. These results demonstrate there is an opportunity to more precisely understand an individual patient’s tumor response using longitudinal plasma testing in order to establish new clinical decision points for the management of patients receiving EGFR inhibitor therapy." Ongoing studies are exploring the outcomes and cost-effectiveness of OncoBEAM RAS testing to guide the management of anti-EGFR treatment in mCRC patients.

Overall, this study shows the value of an ultrasensitive OncoBEAM liquid biopsy RAS test in overcoming sampling bias associated with tissue biopsy to enable rapid turn-around time of molecular test results for more timely initiation of first-line treatment and early detection of RAS mediated resistance in patients receiving anti-EGFR therapy.

The publication, titled "Blood-based RAS mutation testing: concordance with tissue-based RAS testing and mutational changes on progression," was published in Future Oncology July 27, 2020, by Theodora Germetaki, et al. View Source

On August 5, 2020 Aileron Therapeutics (NASDAQ:ALRN) reported business highlights and financial results for the second quarter ended June 30, 2020 (Press release, Aileron Therapeutics, AUG 5, 2020, View Source [SID1234565069]).

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"We continue to make important progress advancing our goal to deliver a novel chemoprotective medicine that can protect cancer patients against multiple serious, often life-threatening chemotherapy-induced side effects," said Manuel Aivado, M.D., Ph.D., President and Chief Executive Officer of Aileron. "We’re pleased with the preliminary data we reported in June from the dose optimization part of our ongoing Phase 1b proof-of-concept clinical trial of ALRN-6924 to protect against chemotherapy-induced bone marrow toxicities in small cell lung cancer patients undergoing treatment with topotecan. These data showed clinically meaningful protection against severe chemotherapy-induced anemia and thrombocytopenia. In addition, a signal of protection against Grade 4 neutropenia in the first treatment cycle was observed at the 0.3 mg/kg dose level."

Dr. Aivado further commented, "Key inflection points for Aileron in the coming months include final Phase 1b dose optimization data in addition to preliminary data from the recently initiated schedule optimization part of the trial, both in the fourth quarter, as well as the initiation of our healthy volunteer study of ALRN-6924 in the third quarter. These milestones will further support and de-risk our plans to expand development of ALRN-6924 for multiple cancer types and various chemotherapies, to ultimately deliver this unique chemoprotective medicine to as many patients with p53-mutated cancers as possible, which could translate to approximately half of all cancer patients."

Key Second Quarter and Recent Highlights

Ongoing ALRN-6924 Proof-of-Concept Phase 1b Study

Part one of study: dose optimization

Announced positive interim dose optimization results. In June 2020, Aileron announced positive interim data from the open-label dose optimization part of its ongoing Phase 1b clinical study of ALRN-6924. The study is evaluating ALRN-6924 as a therapeutic agent administered ahead of chemotherapy to protect against chemotherapy-induced bone marrow toxicities in patients with p53-mutated small cell lung cancer (SCLC) who are being treated with topotecan.
In the dose optimization part of the study, ALRN-6924 was administered at three dose levels (0.3, 0.6, and 1.2 mg/kg) 24 hours before each dose of topotecan. Topotecan was administered days 1 through 5 every 21 days.

As reported in June, treatment with ALRN-6924 resulted in a protective effect against severe chemotherapy-induced anemia and thrombocytopenia compared to historical controls. In addition, patients treated with 0.3 mg/kg ALRN-6924 met the protocol-defined criterion for reduction of NCI CTC Grade 3/4 neutropenia to ≤50% in the first treatment cycle, triggering a cohort expansion at this dose level, from six to 14 patients.

Completed enrollment in dose optimization expansion cohort. Aileron recently announced completion of enrollment into the 0.3 mg/kg dose level cohort expansion, to reach a total of 14 patients treated at this dose and the 24-hour before topotecan schedule
Part 2 of study: schedule optimization

Initiated enrollment in schedule optimization part of study. In June 2020, Aileron announced that it began enrollment in the schedule optimization part of its ongoing Phase 1b clinical study. This part of the study is intended to determine whether ALRN-6924 given six hours before topotecan further enhances the protective effects observed when ALRN-6924 was given 24 hours before topotecan in the dose optimization part of the trial, as described above. Aileron plans to report final dose optimization data, including data from the dose optimization expansion cohort, in the fourth quarter of 2020. In addition, Aileron also plans to report preliminary schedule optimization data in the fourth quarter of 2020. Aileron will continue to carefully monitor the effect of the coronavirus pandemic on its clinical trial sites and the healthcare system, which may impact its planned data announcements.

Planned Healthy Volunteer Study

In the third quarter of 2020, Aileron plans to initiate enrollment in a healthy volunteer study to determine dosing schedules for ALRN-6924 that will support and further de-risk the company’s long-term vision to provide a chemoprotective medicine for patients with p53-mutated cancer regardless of cancer type or chemotherapeutic drug.

Corporate

Completed public offering of common stock. In June 2020, Aileron completed a public offering of common stock, priced at a public offering price of $1.10 per share, raising $10.3 million in aggregate net proceeds, including shares sold to the underwriter pursuant to its exercise of its option to purchase additional shares and after deducting underwriting discounts and commissions and offering expenses.
Second Quarter 2020 Financial Results

Cash Position: Cash, cash equivalents and investments as of June 30, 2020 were $18.9 million, compared to $18.3 million as of December 31, 2019.
Research and Development Expenses: Research and development expenses for the quarter ended June 30, 2020 were $2.5 million, compared to $4.3 million for the quarter ended June 30, 2019. The decrease is primarily a result of a $1.2 million decrease in clinical development expenses attributed to the completion of patient dosing in our Phase 2a expansion cohort of the combination of ALRN-6924 and IBRANCE (palbociclib) for the treatment of MDM2-amplified advanced solid tumors during the first quarter of 2020 and the effect of cost-saving measures implemented in 2019 and 2020.

General and Administrative Expenses: General and administrative expenses were $1.9 million for the quarter ended June 30, 2020, compared to $3.1 million for quarter ended June 30, 2019. The decreased expense in 2020 primarily reflects cost-saving initiatives that were implemented in March 2020 and lower administrative support-related costs in 2020 as compared to 2019.

Net Loss: Net loss was $4.4 million for the quarter ended June 30, 2020, compared to $7.2 million for the corresponding period in 2019.
How ALRN-6924 Works to Protect Healthy Cells from Chemotherapy-Induced Damage

ALRN-6924 is being developed by Aileron as a novel chemoprotective medicine to treat and protect healthy cells in patients with cancer that harbors p53-mutations to reduce or eliminate chemotherapy-induced side effects.

Chemotherapy targets cells that are cycling, or undergoing the process of cell division. In cancer cells, the cell cycle is unchecked, which leads to uncontrolled cell proliferation, a hallmark of cancer. Certain types of healthy cells also naturally need to cycle, such as bone marrow cells (which give rise to red blood cells, white blood cells, and platelets), hair follicle cells, skin cells, and cells lining the oral cavity and the gastrointestinal tract. As a result, chemotherapy targets and kills both cycling healthy cells and cycling cancer cells. This, in turn, leads to a spectrum of chemotherapy-induced side effects, from unpleasant to life-threatening.

ALRN-6924, an investigational first-in-class MDM2/MDMX dual inhibitor, is administered to cancer patients shortly before chemotherapy. ALRN-6924 is designed to selectively activate normal p53 protein in patients’ healthy cells, temporarily and reversibly pausing cell cycling to shield healthy cells from chemotherapy. The protection is limited to healthy cells, as ALRN-6924 cannot work in p53-mutated cancer cells given that p53 has lost function in those cells. Therefore, cancer cells continue to cycle uninterrupted, remaining fully susceptible to destruction by chemotherapy.

On August 5, 2020 GeneCentric Therapeutics, Inc. and Erasmus University Medical Center (EUMC) reported that they have entered into a research collaboration to identify RNA-based drug response markers and novel, targeted therapies in the setting of non-muscle invasive bladder cancer (NMIBC) (Press release, GeneCentric Therapeutics, AUG 5, 2020, View Source [SID1234564815]). The research will comprehensively characterize the tumor and immune biology, as well as the tumor microenviroment related to NMIBC, and will apply GeneCentric’s Bladder Cancer Subtype Profiler (BSP), among other novel assays, to predict disease progression and drug response in these patients.

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The collaboration, led at EUMC by Tahlita Zuiverloon, MD, PhD, Principal Investigator at the Erasmus MC Urothelial Cancer Research Group (EUCRG), will involve the retrospective longitudinal, genomic analysis of samples from a sizeable cohort of NMIBC patients who received surgery and adjuvant treatment. "This collaboration will provide a more complete and fundamental understanding of NMIBC drivers of disease progression, innate and active immune system involvement, and factors related to treatment response and failure or drug resistance," said Dr Zuiverloon. "We look forward to the new insights that the application of GeneCentric’s comprehensive molecular profiling platform can provide as we eagerly pursue new therapeutic options for NMIBC patients."

"To date, genomic subtypes for disease progression risk and drug response to NMIBC have not been well characterized," said Dr. Mike Milburn, President and CEO of GeneCentric Therapeutics. "This exciting research collaboration has potential to augment our molecular gene signatures to help define these subtypes and inform clinical decision making and drug development. There is a significant clinical need and opportunity to improve outcomes, as treatment of NMIBC is evolving with the emergence of novel targeted therapies, potentially including FGFR inhibitors, in addition to the current standard of care."

On August 5, 2020 Verrica Pharmaceuticals Inc. ("Verrica") (Nasdaq: VRCA), a dermatology therapeutics company developing medications for viral skin diseases requiring medical interventions, reported financial results for the second quarter ended June 30, 2020 (Press release, Verrica Pharmaceuticals, AUG 5, 2020, View Source [SID1234563554]).

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"We have made recent key personnel changes that will be important as we work to resubmit the New Drug Application for VP-102, following receipt of a Complete Response Letter from the U.S. Food and Drug Administration. We’re encouraged that the FDA did not raise any clinical safety or efficacy questions, and having recently strengthened leadership in clinical, CMC, and regulatory affairs, we intend to request a Type A meeting with FDA during the third quarter to discuss next steps for resubmission of our NDA. We continue to believe VP-102 can potentially be approved as a safe, effective treatment for molluscum," said Ted White, Verrica’s President and Chief Executive Officer.

Business Highlights and Recent Developments

Verrica received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the New Drug Application (NDA) for VP-102, in which the FDA requested additional information regarding certain aspects of the CMC (Chemistry, Manufacturing, and Controls) process, as well as Human Factors validation. The Agency noted no clinical safety or efficacy deficiencies were identified. Verrica intends to request a Type A meeting with the FDA during the third quarter of 2020, and is committed to working to resubmit the NDA as quickly as possible.

The Company announced changes to its Board of Directors, as well as its CMC, and Regulatory Affairs leadership. Dr. Lawrence Eichenfield, a leading pediatric dermatologist, has been appointed to the Board. Dr. Eichenfield replaces Dr. Gary Goldenberg, who stepped down from the Board to assume the role of Verrica’s Chief Medical Officer. The Company also appointed Dr. Brad Catalone to the newly created position of Head of Drug Development.

Verrica entered into an Option Agreement with Torii Pharmaceutical Co., Ltd. (Torii) for the development and commercialization of Verrica’s product candidates for the treatment of molluscum contagiosum and common warts in Japan, including VP-102. Under the terms of the Option Agreement, Torii will pay Verrica USD $500,000 to secure the exclusive option. Torii may exercise the option to obtain exclusive license rights until the later of six months after the effective date of the Option Agreement, or ten business days after the Company notifies Torii that the FDA has accepted for filing the Company’s resubmission of the NDA for VP-102. If Torii exercises the option, the license agreement would provide for Torii to make an up-front payment of $11.5 million, up to an additional $58 million in aggregate payments contingent on achievement of specified development, regulatory, and sales milestones, and tiered transfer price payments for supply of product in the percentage range of the mid-30s to the mid-40s of net sales. Torii would be responsible for all development activities and costs in support of obtaining regulatory approval in Japan.

Two new pooled analyses of the Phase 3 CAMP trials of VP-102 in molluscum were presented as online posters at the virtual American Academy of Dermatology 2020 Annual Meeting. A pre-specified exploratory analysis showed VP-102 brought about a statistically significant percentage of patients with complete molluscum lesion clearance across all lesion count quartiles compared to vehicle. An additional post-hoc analysis showed any patient with baseline characteristics matching study protocol may be a candidate for complete lesion clearance after up to four VP-102 treatments.
Second Quarter 2020 Financial Results

Verrica reported a net loss of $9.4 million for the second quarter of 2020, compared to a $7.0 million net loss for the same period in 2019.
Research and development expenses were $3.5 million in the second quarter of 2020, compared to $3.9 million for the same period in 2019. The decrease was primarily attributable to decreased costs related to Verrica’s development of VP-102 for molluscum contagiosum, partially offset by increased compensation costs.
General and administrative expenses were $5.1 million in the second quarter of 2020, compared to $3.6 million for the same period in 2019. The increase was primarily a result of expenses related to increased headcount, an increase in insurance, professional fees and other operating costs, and an increase in expenses related to pre-commercial activities for VP-102.
Year-to-Date June 2020 Financial Results

Verrica reported a net loss of $19.2 million for the six months ended June 30, 2020, compared to a $14.5 million net loss for the same period in 2019.
Research and development expenses were $8.4 million for the six months ended June 30, 2020, compared to $8.4 million for the same period in 2019.
General and administrative expenses were $10.1 million for the six months ended June 30, 2020, compared to $7.1 million for the same period in 2019. The increase was primarily a result of expenses related to increased headcount, an increase in insurance, professional fees and other operating costs, and an increase in expenses related to pre-commercial activities for VP-102.
As of June 30, 2020, Verrica had aggregate cash, cash equivalents, and marketable securities of $79.6 million, which the Company believes will be sufficient to support planned operations at least through the fourth quarter of 2021.

On August 5, 2020 Takeda reported took a slap from the FDA in June when inspectors slammed its Hikari, Japan, plant in a warning letter (Press release, FiercePharma, AUG 5, 2020, View Source [SID1234563250]). It turns out that fixing those problems helped trigger a local shortage of the chemotherapy drug leuprorelin—and now, the drugmaker is scrambling to shore up supply to keep the shortage from spreading.

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The June warning letter cited Hikari for poor equipment maintenance, faulty documentation and quality shortfalls. Working with the FDA to fix those problems, Takeda had to periodically stop production at the plant for remediation.

"We have a very strong expertise and background in quality," CEO Cristophe Weber said during the company’s quarterly earnings call. "So we know how to resolve this situation. We have a very clear path to … remediate the situation in Hikari."

Production stoppages naturally mean less output, and leuprorelin supply is suffering, the company said during its quarterly earnings presentation Friday. Manufacturing for the Japan market resumed July 20, and the company expects to resupply the drug there in September.

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"We really are aiming to reduce the potential impact, the potential shortage for patients," Weber said during the earnings call. "We gave some guidance to the doctors in Japan to manage as well as possible their patients. So I apologize to the doctors, to the patients, about the inconvenience, but I think we are doing really our best to limit that impact."

Takeda’s earnings presentation said it anticipates a "temporary supply shortage" of leuprorelin in Japan, and "certain regions, including the U.S., may experience periodic shortages." The drug is a synthetic hormone used to fight prostate cancer, breast cancer, endometriosis, uterine fibroids and early puberty.

Listed by the U.S, FDA as leuprolide acetate, the drug is sold by AbbVie—once Takeda’s marketing partner on the drug—under the Lupron brand and Tolmar Pharma as Eligard and Fensolvi. According to the agency’s current catalog of drug shortages, various doses of AbbVie’s version are unavailable or on back order in the U.S.

Takeda said it doesn’t expect a global shortage of leuprorelin; it manufactures the drug for the European market at a plant in Osaka.

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The Hikari plant also produces Takeda’s ulcerative colitis therapy Entyvio, but several other facilities worldwide also turn out the drug, and the company said it does not expect any shortages. The plant was last inspected in 2017 with no problems found.

Meanwhile, Takeda is working with the FDA to fix the problems highlighted in the warning letter. It has brought in external consultants to help fashion a corrective action plan, the presentation slide said.

It will take time, however, as Weber noted on the earnings call. The audit took place in November 2019, Weber said, and typical remediation work takes 12-18 months. "That’s what we are seeing right now at Takeda. We believe that within 12 months, we will be ready for inspection," the CEO said, predicting an inspection-ready status by year’s end. "And we’ll have remediated the issues."