Cancer-killing virus flees immune destruction and attacks metastatic lung tumors; Urovant’s vibegron fails trial; Genmab discards antibody-drug conjugate; Polyphor picks up $3.3M for inhaled antibiotic

Cancer-killing virus flees immune destruction and attacks metastatic lung tumors in mice

Several viruses have a natural ability to eliminate cancer; however translating them into treatments has proven difficult, partly due to the immune system tends to kill them before they can reach cancer cells. Researchers from Emory and Case Western Reserve state they have got a method to succeed that challenge with a specially engineered virus.

The team took human adenovirus and re-engineered it so the immune system cannot capture it and sent to the liver for destruction, in mouse models of metastatic lung cancer, the virus prolonged survival. About 35% of the animals were cleared of their tumors as reported in Science Translational Medicine.

There is one oncolytic virus on the market, Amgen’s Imlygic, a herpes-derived treatment, which can be useful when injected squarely into melanoma lesions. However, it mostly does not work in patients with metastatic disease.

Urovant’s vibegron fails Irritable bowel syndrome phase 2 trial

A phase 2a clinical trial of vibegron of Urovant in Irritable bowel syndrome (IBS) patients has flunked primary endpoint. The problem depresses the prospects of Urovant in one indication but still leaves it set up to secure approval in overactive bladder and be taken over by Sumitovant Biopharma.

Urovant has commenced a multifront R&D campaign since buying small molecule beta-3 agonist vibegron from Merck in 2017. The drug did not do any better than a generic control in a phase 3 trial in overactive bladder patients. However, Urovant progressed quickly for filing for FDA approval earlier this year in a bid to set vibegron as a rival to beta-3 agonist Myrbetriq of Astellas.

The prospects of Urovant finally adding IBS to the list of conditions treated by vibegron experienced a hit when the company disclosed a phase 2a trial fails its primary endpoint. 

Genmab discards antibody-drug conjugate after the early-phase fiasco

Genmab is ditching an antibody-drug conjugate after it flunked the mark in early-phase trials.

The candidate, enapotamab vedotin, aims AXL, which is overexpressed in multiple blood cancers and solid tumors. It did present some evidence of clinical activity, but its promise did not support in different dosing regimens or biomarkers. Hence it got exited from Genmab’s pipeline.

The move comes after Genmab pulled off a USD 506 million Nasdaq IPO, part of which was for a fund to enapotamab vedotin. The rest of the funds would bankroll the development of tisotumab vedotin and take it to the market, and drive other programs through the clinic.

Terminating enapotamab vedotin will allow the resources for Genmab’s other prospects, as said by CEO Jan van de Winkel, PhD, in the statement. That covers Seagen-partnered tisotumab vedotin, which is in phase 2 for cervical and ovarian cancers and other solid tumors.

Polyphor picks up USD 3.3 Million from Cystic Fibrosis Foundation for inhaled antibiotic

Polyphor snagged a USD 3.3 million from the Cystic Fibrosis Foundation in order to develop an inhaled antibiotic for lung infections, which are often fatal in people with cystic fibrosis.

The funds will bankroll a phase 1b/2a study of an inhaled version of murepavadin, an antibiotic, which aims multidrug-resistant Pseudomonas aeruginosa infections. The drug is presently delivered intravenously, so an inhaled version could make it possible for treating patients outside of a hospital or clinic. 

J.P. Clancy, M.D., vice president of clinical research at the Cystic Fibrosis Foundation said in a statement that a remarkable number of Cystic Fibrosis people have multi-drug resistant strains of Pseudomonas each year that require IV antibiotics and hospitalization. They hope to determine whether the inhaled version of this new medicine could confer an alternative treatment option for Cystic Fibrosis people that could potentially decrease their treatment burden.

Murepavadin aims Pseudomonas, targeting its outer membrane that could give it an advantage to other inhaled antibiotics. The latter can usually resist Pseudomonas infections, but as they target a broad spectrum of bacteria, can also contribute to the increase of antibiotic-resistant bugs.

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Merck, Dewpoint’s HIV Pipeline; Pfizer, BioNTech ‘s COVID-19 Vaccines; Roche’s Tecentriq- Avastin Duo Failure in Ovarian Cancer

Merck Collaborates with Dewpoint Therapeutics to Cure HIV with Condensates  

Merck has forged a collaboration with Boston-based Dewpoint Therapeutics to treat HIV using Dewpoint’s proprietary platform for condensate-based drug discovery.
Under the terms of the agreement, Dewpoint is eligible for receiving up to an upfront amount of USD 305 Million along with milestone payments as well as royalties on sales of products.

Dewpoint was launched last year to explore and uncover novel mechanisms to treat one of the most devastating diseases – HIV. Dewpoint’s condensate platform explores the ability of condensates in curing HIV. Earlier Dewpoint also announced a USD 100 Million deal with Bayer to develop novel therapies for cardiovascular and gynaecological diseases.

Merck already homes the FDA-approval for two HIV treatments Delstrigo and Pifeltro, both of which are treatments for HIV-1 in patients with no prior antiretroviral therapies. Recently, Merck presented the data of Phase IIb trials for its Islatravir in combination with doravirine for HIV-1 infection. The collaboration with Dewpoint will surely bolster Merck’s HIV-1 infection pipeline further.

Pfizer, BioNTech mRNA-based Vaccines Against SARS-CoV-2 Receives FDA’s Fast Track Designation

The US FDA has given Fast Track Designation to two of the COVID-19 vaccine candidates, BNT162b1 and BNT162b2, jointly developed by Pfizer and BioNTech.

Currently, the vaccines are in Phase I/II study. Both the investigational vaccines BNT162b1 and BNT162b2 are nucleoside-modified RNAs, formulated in lipid nanoparticles. BNT162b1 encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen, whereas BNT162b2 encodes an optimized SARS-CoV-2 full-length spike protein antigen.

The decision of the FDA was based on the early data from the trials evaluating these two vaccines in the BNT162 program presented earlier this month. The designation will help in speedy approval of the preventive therapy against SARS-CoV-2, that has clutched the whole world in its paws. If the further process goes without any obstructions, the companies plan to file for regulatory approval of vaccines by the end of 2020.

Roche’s Tecentriq- Avastin Duo Flops to Keep Ovarian Cancer Away

Genentech, a Roche’s subsidiary announced the failure of its combination of Tecentriq (atezolizumab) – anti-PD-L1 checkpoint inhibitor, and Avastin (bevacizumab) – an antibody that binds to VEGF, as they missed the primary endpoint in Phase II trials (IMagyn050) indicated for newly-diagnosed advanced-stage ovarian cancer as front-line treatment.

The trial is evaluating the combination of Tecentriq with Avastin, plus chemotherapy drugs – paclitaxel and carboplatin compared to placebo plus Avastin, paclitaxel and carboplatin in stage III or IV ovarian cancer patients who are receiving neoadjuvant or adjuvant therapy.

However, the safety profile of the combo was in line with the previous results; hence, the company plans to further proceed with the trials, and the therapy still has a chance to hit co-primary endpoints, which are investigator-determined PFS and OS for two different groups, the intent-to-treat (ITT) population and the PD-L1-positive subpopulation.

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Rising Popularity of Drug Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer Indications

Cancer is considered to be the second leading cause of mortality, after cardiovascular diseases, accounting for every sixth reported death in the world. The International Agency for Research on Cancer (IARC) states that the number of new cancer cases is expected to grow to 27.5 million across the globe, by 2040. Experimental evidence has shown that defects in the deoxyribonucleic acid (DNA) repair machinery are one of the primary causes for both generation and maintenance of cancer. It is a well-known fact that DNA is the reservoir of genetic information in all cells. Defects in deoxyribonucleic acid (DNA) repair have been shown to be one of the primary causes of cancer. Moreover, tumor cells that are characterized by impaired DNA repair pathways typically become reliant on alternative DNA repair pathways for survival. This phenomenon is commonly referred to as oncogene addiction. 

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer  Indications

What is the Basic Concept of Synthetic Lethality?

Inhibitors of such compensatory repair pathways have the potential to sensitize cancer cells to DNA damaging agents and other therapeutic regimens. On the other hand, the simultaneous inactivation of certain pairs of genes have been shown to cause cell death. This phenomenon is known as synthetic lethality. In cancers, where mutations have led to the loss of function of one gene, using a drug molecule that specifically targets the corresponding gene of the synlet pair has been demonstrated to be a viable and effective therapeutic regimen.

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer  Indications

What is the recent activity on Social Media Platforms?

Further, recent activity on Twitter (2,100+ tweets) confirms the rising interest in this domain as stakeholders attempt to harness the therapeutic potential of synthetic lethality. In addition to PARP inhibitors / BRCA mutations, ATM, ATR, CHK1, KRAS and RAD51, are presently considered amongst the most prominent synlet targets, which are being investigated in the clinical stages of development. Further, CDK12, PI3K, PLK1, PTEN, SNF and WRN are synlet targets that are currently being evaluated in preclinical studies.

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer  Indications

What are the most popular synlet targets being explored for drug development?

Significant advances in research have led to the discovery of a wide array of synlet targets; over time, substantial intellectual capital has been generated and validated by eminent scientists from renowned research institutes. Specifically, 55+ targets are already clinically / preclinically validated, while over 160 targets have been mentioned in various research publications (with no drug candidate so far).

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer  Indications

Recent Approvals: Drug Watch 2020

It is worth noting that, till date, only four molecules have been marketed, namely olaparib (2014), rucaparib (2016), niraparib (2017) and talazoparib (2018). Recently, in April 2020, the USFDA approved GSK’s PARP inhibitor, niraparib, for expanded use as a maintenance therapy in advanced ovarian, fallopian tube, or primary peritoneal cancer patients in complete or partial response to frontline platinum-based chemotherapy. In January 2020, the USFDA granted priority review designation to a supplemental new drug application (sNDA) for olaparib as maintenance therapy in advanced ovarian, fallopian tube, or primary peritoneal cancer patients in complete or partial response to frontline platinum-based chemotherapy. In January 2020, NICE recommended olaparib for use in the NHS for BRCA-positive patients in the second-line, post-platinum-chemotherapy treatment setting for ovarian cancer. In January 2020, the USFDA granted fast track designation to Clovis Oncology’s rucaparib for prostate cancer. In addition, two molecules, veliparib (developed by AbbVie) and pamiparib (developed by BeiGene), are in phase III of development and are likely to reach the market in the near future.

How is the current and estimated opportunity segmented across key market segments?

The present market is driven by the sales generated by four approved PARP inhibitors, niraparib, olaparib, rucaparib and talazoparib. Future growth of the market is likely to be driven by the success of clinical outcomes of late-stage molecules; industry stakeholders are optimistic about the vast potential of PARP inhibitors.

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer  Indications

To get detailed insights on the key players, synlet targets, funding and investment trends research landscape, recent developments and the likely market evolution, check out the report here

Rising Popularity of Drugs Targeting Synthetically Lethal Targets Fuels the Battle of PARP Inhibitors for Treatment of Advanced Cancer Indications

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