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Oncopeptides submits a New Drug Application to the FDA for accelerated approval of melflufen in triple-class refractory multiple myeloma patients

On June 30, 2020 Oncopeptides AB (publ) (Nasdaq Stockholm: ONCO) reported that the Company submits a New Drug Application (NDA) to the U.S. Food and Drug Administration, FDA, for accelerated approval of melflufen (INN melphalan flufenamide) in combination with dexamethasone for the treatment of adult patients with multiple myeloma whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent and one anti-CD38 monoclonal antibody (i.e., triple-class refractory multiple myeloma patients) (Press release, Oncopeptides, JUN 30, 2020, View Source [SID1234561555]).

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Melflufen is the lead candidate coming out of the Oncopeptides’ proprietary PDC-platform. The product is a first-in-class aminopeptidase-targeting peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. The submission is based on the results from the pivotal phase 2 study HORIZON, evaluating intravenous melflufen in combination with dexamethasone in patients with relapsed refractory multiple myeloma (RRMM).

The results from the HORIZON study demonstrates that melflufen in combination with dexamethasone, has a potential to provide a therapeutic option for patients with RRMM that are hard to treat and have a poor prognosis, including patients with triple class refractory myeloma and patients with extramedullary disease (EMD). The responses in the HORIZON study were durable and often deepened with prolonged treatment, suggesting that patients could benefit from staying on treatment for as long as possible.

"I am very proud and humbled by the organizations ability to timely submit the NDA for accelerated approval of melflufen. This is a major milestone for Oncopeptides and is a result of dedicated research and development activities throughout the last decade", says Jakob Lindberg CEO of Oncopeptides. "I would like to express my sincere gratitude to all patients, co-workers, investigators and shareholders who have provided relentless support to enable a novel treatment option for a fast-growing patient population with a significant unmet medical need".

Following the submission to the FDA Oncopeptides will initiate an Expanded Access Program (EAP) in the U.S. to enable melflufen treatment for patients with a significant unmet medical need.

About the HORIZON study
In total 157 multiple myeloma patients have been enrolled and evaluated in the pivotal phase 2 HORIZON study. The study was fully recruited in October 2019, the final data cut was made on January 14th and the final data was presented at the EHA (Free EHA Whitepaper) meeting in June. The patients in the study were refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). The HORIZON study population includes subgroups of patients who were triple?class refractory and/or had extramedullary disease and/or had cytogenetic high?risk features.

Summary of results

End Points Intention to Treat (n=157) Triple Class Refractory (n=119) Extra Medullary Disease (n=55)
Overall Response Rate (ORR) 29% 26% 24%
Median Progression Free Survival (PFS)) 4.2 months 3.9 months 2.9 months
Median Overall Survival (OS) 11.6 months 11.2 months 6.5 months
Responding patients n=45 n=31 n=13
Median Duration of Response (DOR) 5.5 months 4.4 months 5.5 months
Median Progression Free Survival (PFS) 8.5 months 8.5 months 17.3 months
All data were confirmed by the Independent Review Committee (IRC), with only minimal discordance.

About melflufen
Melflufen (INN melphalan flufenamide) is a first-in-class aminopeptidase-targeting peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately hydrolyzed by peptidases to deliver an entrapped hydrophilic alkylator payload. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

Expanded access policy
The preparations for an Expanded Access Program (EAP) in the US are well underway and the program will open in Q3. Oncopeptides encourages awareness of and participation in its clinical trials and believes that participating in clinical trials is a good way for patients to access investigational drugs prior to regulatory approval. Individuals interested in participating in clinical trials for melflufen may visit View Source for information about ongoing clinical trials. Patients are encouraged to consult their physician regarding the possibility of participating in one of the ongoing clinical trials.

Chugai Files a New Drug Application for Polatuzumab Vedotin for the Treatment of Relapsed or Refractory Diffuse Large B-cell Lymphoma

On June 30, 2020 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW) for polatuzumab vedotin, an anti-CD79b antibody-drug conjugate, for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) on June 29 (Press release, Chugai, JUN 30, 2020, View Source [SID1234561537]). Polatuzumab vedotin received orphan drug designation from MHLW in November 2019.

"About 40% of patients with untreated DLBCL experience relapse of the disease after standard therapy and subsequent treatment options are limited. In many cases, therapeutic effects on relapsed or refractory DLBCL are insufficient, and there is a high unmet medical need" said Dr. Osamu Okuda, Chugai’s President and COO. "Polatuzumab vedotin is a therapeutic antibody which bolsters Chugai’s blood cancer franchise following Rituxan and Gazyva. We will continue our efforts to deliver polatuzumab vedotin, an antibody-drug conjugate with a novel mechanism of action, to patients as early as possible and contribute to the realization of better treatment."

This application is based on the results from a multicenter, single-arm Japanese phase II study (JO40762/P-DRIVE study) that evaluated the efficacy and safety of the combination therapy of polatuzumab vedotin with bendamustine and rituximab (BR therapy) in relapsed or refractory DLBCL, and a multicenter overseas phase Ib/II clinical study (GO29365) comparing the efficacy and safety of polatuzumab vedotin in combination with BR therapy to BR therapy. A double-blind, placebo-controlled global phase III study (GO39942/POLARIX study) is ongoing for untreated DLBCL to compare the efficacy and safety of polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, prednisolone (R-CHP) to rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP).

[Reference information]
Polatuzumab Vedotin Achieved Primary Endpoint in the Japanese Phase II study for Relapsed or Refractory Diffuse Large B-cell Lymphoma (Press release issued by Chugai on February 13, 2020)
View Source

European Commission approves Roche’s Policy for people with previously treated aggressive lymphoma (Press release issued by Roche on January 21, 2020)
View Source

Chugai Receives Orphan Drug Designation for Polatuzumab vedotin in Diffuse Large B-Cell Lymphoma from the MHLW (Press release issued by Chugai on November 20, 2019)
View Source

About polatuzumab vedotin
Polatuzumab vedotin was developed by Roche using Seattle Genetics’ ADC technology. It is a first-in-class anti-CD79b antibody-drug conjugate (ADC), comprising the anti-CD79b humanized monoclonal antibody and a tubulin polymerization inhibitor attached together using a linker. The CD79b protein is expressed specifically in the majority of B-cells, making it a promising target for the development of new therapies1, 2). Polatuzumab vedotin binds to CD79b and destroys these B-cells through the delivery of an anti-cancer agent, which is thought to suppress the effects on normal cells3, 4). Polatuzumab vedotin was granted accelerated approval in the US in June 2019 and conditional marketing authorization in the EU in January 2020, respectively.

About diffuse large B-cell lymphoma (DLBCL)
DLBCL is one of the histologic subtypes of non-Hodgkin’s lymphoma (NHL), which is categorized as an aggressive disease that progresses on a monthly basis. DLBCL is the most common form of NHL, accounting for 30-40 percent of NHL5-7). DLBCL frequently occurs in middle-aged and older people, mainly in their 60’s8). The median age at diagnosis has been reported to be 649).

The combination of rituximab and chemotherapy is the standard therapy for untreated DLBCL; however, recurrence has been observed in about 40% of the patients due to insufficient therapeutic effect10). In addition, although autologous stem cell transplantation (ASCT) is recommended in eligible patients with recurrent or refractory DLBCL, ASCT cannot be performed in about half of these patients due to failure of salvage chemotherapy prior to ASCT11). Furthermore, no standard therapy has been established for patients ineligible for ASCT due to reasons including age or complications12). Therefore, more useful new treatment options for relapsed or refractory DLBCL are in great need.

Sources

Dornan D, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 2009; 114:2721-2729
Pfeifer M, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; 29:1578-1586
Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010; 21:5-13
ADC Review. What are antibody-drug conjugates? Available from: View Source (accessed in June 2020)
Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th Edition. Lyon, International Agency for Research on Cancer; 2017
Aoki R, et al. Distribution of malignant lymphoma in Japan: Analysis of 2260 cases.2001-2006. Pathol Int 2008; 58(3):174-182
Chihara D, et al. Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol 2014 Feb; 164(4):536-545
Niitsu N, Diffuse large B-cell lymphoma. The Journal of the Japanese Society of Internal Medicine 2008; 97:1588-1594
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 1998; 16:2780-2795
Friedberg JW. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505
Gisselbrecht C, et al. Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era. J Clin Oncol 2010; 28: 4184-4190
Japanese Society of Hematology. Practical Guidelines for Hematological Malignancies, 2018, Kanehara & Co., Ltd. (Japanese only)

The result of pre-clinical trial of ‘PI3K·DNA-PK inhibiting anti-cancer drug’ from Boryung Pharmaceutical

On June 29, 2020 Boryung Pharmaceutical is developing BR101801 (project name BR2002) is an anti-cancer drug which simultaneously inhibits PI3K (γ/δ) and DNA-PK, showed its potential as a treatment in various solid cancer models as well as in blood cancer (Press release, Boryung Pharmaceutical, JUN 29, 2020, View Source [SID1234644864]).

Boryung Pharmaceutical unveiled some of the pre-clinical trial results of BR101801 at the annual conference of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which was held online on the 22nd (local time).

PI3K (phosphoinositide3-kinase) is an enzyme that regulates intracellular signal transduction process and regulates multiple functions such as cell growth, proliferation and differentiation, migration, and survival. As an enzyme that recognizes and repairs DNA damage in cells, DNA-PK helps cancer cells survive despite of DNA damage.

BR101801, solely developed by Boryung Pharmaceutical, is a target anti-cancer agent and cancer immunotherapy agent that simultaneously inhibits PI3K and DNA-PK. In this AACR (Free AACR Whitepaper), Boryung Pharmaceutical released total of 3 posters of which are related to cancer cell death of BR101801: efficacy in monotherapy and combined therapy, efficacy as an cancer immunotherapy drug, ability to inhibit repair factor of cancer cell damage.

Boryung Pharmaceutical not only uses BR101801 alone but also BR101801+ anti PD-1, BR101801+ anti PD-L1, BR101801+ OX40, BR101801+ Doxorubicin in various animal models such as liver cancer, breast cancer, lung cancer and colon cancer models. As a result of combination therapy, efficacy of BR101801 in terms of survival rate and tumor size was confirmed as compared with the control group.

Boryung Pharmaceutical has also conducted a mono and combined efficacy study of BR101801 on cancer cell deaths from peripheral blood mononuclear cells (human PBMCs). Gilead’s Zydelig (Idelalisib), Verastem’s Copiktra (Duvelisib) and other drugs that have been approved as PI3K inhibitors to date have been set as a control group for comparative studies. As a result, it was confirmed that BR101801 showed superior efficacy in killing cancer cells and controlling c-Myc (tumor-inducing gene) compared to the controls from 52 hematological cancer cell lines.

Especially when BR101801 alone is administered, Treg (regulatory T cells) and MDSC (bone marrow-derived suppressor cells), which are immunosuppressive cells, are decreased, and CD8+, which is an immune cell that kills cancer cells, is increased. It has confirmed its effects of a cancer immunotherapy agent. Also, it showed the effect of inhibiting DNA-PK, which is an enzyme involved in recognizing DNA damage in cancer cells and involved in repair, and showed the effect of killing cancer cells.

The researcher team said, "BR101801 has been shown to have the effect of killing cancer cells not only in blood cancer but also in various solid cancers when co-administered with cytotoxic anti-cancer drug or through the radiation."

Boryung Pharmaceutical said BR101801 has been currently undergoing 1st clinical phase for the indication of non-Hochkin’s lymphoma, a type of blood cancer, simultaneously in Korea and in the U.S. since this March.

Cambridge Spin-out PharmEnable Raises £1.8 million for Drug Discovery Expansion

On June 29, 2020 PharmEnable, a Cambridge-based drug discovery company using advanced medicinal chemistry and AI-enabled approaches to design the next generation of highly complex and specific drug candidate molecules, reported it has closed a £1.8 million seed financing to support its transition into a drug development company (Press release, PharmEnable, JUN 29, 2020, View Source [SID1234641051]). It aims to develop new treatments for conditions with significant unmet clinical need, by designing highly complex molecules for addressing challenging biological targets. The round, which was significantly over-subscribed, was led by Cambridge Enterprise, the commercialisation arm of the University of Cambridge, as well as the University of Cambridge Enterprise Fund VI, managed by Parkwalk Advisors. It also attracted support from a wealth of angel investors and notable life science funds, including Jonathan Milner, serial entrepreneur and founder of Abcam; Andy Richards, Cambridge-based entrepreneur and investor; David Ford, Oxford-based life sciences angel investor; the family office of Paul Forster, co-founder of Indeed.com; Ian Tomlinson, chairman of several bio-incubators, entrepreneur and co- founder of Domantis; KQ Labs at the Francis Crick Institute; Martlet Capital, a Cambridge-based investor with a growing portfolio of innovative life science companies; the fast-growing o2h ventures Human Health EIS fund; and Wren Capital, the established London-based angel investor in science, engineering and software businesses. A spin-out from the University of Cambridge in 2016, and financed to date by its founders and service-based revenues, PharmEnable will use the funding to evolve its business model and invest in a pipeline of drug discovery programmes across a number of disease areas including cancer and neurodegenerative disease. Additionally, PharmEnable will continue to engage in strategic partnerships with pharma, innovative biotechs and academia. PharmEnable is led by co-founder and CEO Dr Hannah Sore. It has attracted an experienced Board and management team including Dr Jane Dancer, previously of F-star, who joined recently as the new Board Chair. The financing has enabled PharmEnable to expand its scientific team including Dr David Vidal as Director of Technology, with further expansion, including the addition of a Director of Drug Discovery planned for Q3 2020. The PharmEnable platform technology can predict improved small molecule hits to targets across a range of disease areas. Its approach focuses on exploring and mapping the possible chemical universe and designing novel small molecules that are highly complex with shapes similar to those found in nature. This approach can identify hits with improved specificity compared with traditional screening methods, and allows PharmEnable to take on particularly challenging biological targets, such as protein-protein interactions and epitranscriptomic modifications that have been undruggable by existing approaches. Its solution consists of two elements: ChemUniverse a diversity-focused virtual database of chemically diverse molecules; and ChemSeek, a suite of gold standard AI-enabled tools for finding drug target matches from structure and ligand data.

Commenting on the financing, CEO of PharmEnable Dr. Hannah Sore said:

"We are pleased to welcome on board our new investors and appreciate their confidence in our business. Our aim is to replicate the specificity of biologics in the powerful and scalable form of a small molecule, to treat devastating diseases where there are currently no treatment options. We have proven the strength of our platform in tapping unexplored parts of the chemical universe to find novel and specific hits for currently undruggable targets, and are excited to now be able to invest in our own pipeline of drug discovery programmes, as well as to develop further strategic partnerships."

Dr Christine Martin, Head of Life Science Investment at Cambridge Enterprise said:

"Cambridge Enterprise is really pleased to be investing in this exciting opportunity. To have closed the round during these last few months, and to have attracted such a strong investor syndicate, is a testament to the potential of the AI-enabled platform that PharmEnable has built. We are pleased to support the Company in its transition to in-house drug discovery. We believe the company will have significant impact through addressing undruggable therapeutic targets."

Following the investment, Dr Christine Martin, Head of Life Science Investment at Cambridge Enterprise and Peter McPartland, Investment Director of Martlet Capital and representative for all other investors, join the board of directors of PharmEnable, alongside Dr Jane Dancer (independent Chair), Dr Hannah Sore (CEO) Dr Natalia Mateu (CSO) and Gaynor Fryers (independent NED). David Ford also serves as a Board Observer for the entrepreneurs/angel investors.

Aileron Therapeutics Initiates Enrollment in Schedule Optimization Part of Phase 1b/2 Study of ALRN-6924 as a Chemoprotection Agent in Small Cell Lung Cancer (SCLC) Patients Being Treated with Topotecan

On June 29, 2020 Aileron Therapeutics (NASDAQ:ALRN), a biotechnology company advancing a novel chemoprotective therapy for cancer patients, reported that it has enrolled the first patient in the open-label Phase 1b schedule optimization part of its ongoing Phase 1b/2 clinical trial, evaluating ALRN-6924’s potential to protect patients against chemotherapy-induced toxicities (Press release, Aileron Therapeutics, JUN 29, 2020, View Source [SID1234565066]). Patients in this open-label trial have p53-mutated extensive disease small cell lung cancer (SCLC) and are being treated with second-line topotecan following administration of ALRN-6924. The schedule optimization part of the trial is intended to determine whether ALRN-6924 given six hours before topotecan further enhances the protective effect of ALRN-6924 against severe hematological adverse events observed when ALRN-6924 was given 24 hours before topotecan in the dose optimization part of the trial, as reported by Aileron earlier this month.

"Following our recent announcement of positive interim data from the Phase 1b dose optimization part of this ongoing Phase 1b/2 study, we are pleased to reach another key milestone in our advancement of ALRN-6924 to potentially transform the treatment paradigm for cancer patients undergoing chemotherapy," said Manuel Aivado, M.D., Ph.D., President & CEO of Aileron Therapeutics.

Dr. Aivado explained, "Chemotherapy remains a critical cornerstone treatment for millions of cancer patients. Unfortunately, in the process of killing cancer cells, chemotherapy inadvertently harms healthy cells, too. This leads to a multitude of common, damaging, severe toxicities. We treat healthy cells ahead of chemotherapy to prevent those toxicities, importantly, without interrupting chemotherapy’s potent onslaught against cancer cells. ALRN-6924 could dramatically improve patients’ quality of life by improving their tolerance to chemotherapy."

ALRN-6924’s novel mechanism of action leverages the innate ability of intracellular p53 protein to induce cell cycle arrest in healthy cells to prevent toxicities driven by chemotherapy’s off-target effects in bone marrow and potentially other tissues and organs. In patients with p53-mutant cancers, which represent approximately 50% of all cancer patients, ALRN-6924 is designed to shield healthy cells from chemotherapy while preserving the susceptibility of cancer cells to chemotherapy.

About the Phase 1b/2 Study

The ongoing Phase 1b/2 study is designed to identify an optimal dose and schedule of ALRN-6924 administration to reduce chemotherapy toxicities such as severe anemia, thrombocytopenia, and neutropenia caused by topotecan in patients with small cell lung cancer. There are two parts to the Phase 1b study: (i) dose optimization and (ii) schedule optimization.

In the dose optimization part, which enrolled 18 patients, ALRN-6924 was administered at three dose levels (0.3, 0.6, and 1.2 mg/kg) 24 hours before each dose of topotecan on days 1 through 5 of every 21-day treatment cycle. An expansion cohort of the dose optimization part of the trial at the 0.3 mg/kg dose level is ongoing.

Aileron announced positive interim findings from this part of the trial in June 2020. ALRN-6924 demonstrated a protective effect against severe chemotherapy-induced anemia and thrombocytopenia across all dose levels as compared to historical controls. In addition, patients treated with 0.3 mg/kg ALRN-6924 met the protocol-defined criteria for reduction of NCI CTC Grade 3/4 neutropenia to ≤50% in the first treatment cycle triggering the expansion cohort in up to eight patients.

In the schedule optimization part, ALRN-6924 is being administered at two dose levels (0.3 and 0.6 mg/kg) 6 hours before each dose of topotecan on days 1 through 5 of every 21-day treatment cycle. Aileron expects to enroll approximately 20 patients in this part of the study.
"We were highly encouraged by the strong chemoprotective effect of ALRN-6924 seen in the dose optimization part of this study as previously reported, as it reinforces our belief that ALRN-6924 can selectively induce cell cycle arrest to protect cancer patients from the toxic side effects of chemotherapy," said Vojo Vukovic, M.D., Ph.D., Chief Medical Officer of Aileron. "The schedule optimization part of the trial is intended to inform whether ALRN-6924 given six hours before topotecan can further enhance the protective effects we have observed when giving our drug 24 hours before topotecan."

Phase 1b/2 Trial – Next Steps

While enrollment in the 6-hour dosing schedule is underway, Aileron is continuing to enroll patients in the expansion cohort of its 0.3mg/kg dose level using the 24-hour schedule.

As previously reported, the company plans to report topline data from the schedule optimization and final data from the dose optimization parts of the trial in the fourth quarter of 2020. Aileron expects that these results will enable the company to determine a recommended ALRN-6924 dose and schedule for subsequent trials.

Aileron is carefully monitoring the effect of the coronavirus pandemic on its clinical trial sites and the healthcare system, which may impact the future timing of the trial and the company’s planned data announcements.

About ALRN-6924
ALRN-6924 is a first-in-class dual MDM2/MDMX inhibitor that is currently being evaluated in a Phase 1b/2 clinical trial as a chemoprotective agent to protect against chemotherapy-related toxicities.