15 February 2019

Canadian researchers develop molecules to reverse memory loss

Researchers at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, have developed new therapeutic small molecules that could potentially reverse memory loss caused due to depression and ageing.

The molecules have been designed to bind to and activate the GABA receptor.

This is intended to fix the impairments in the GABA neurotransmitter system that are implicated to be associated with mood and memory symptoms in depression and ageing.

The molecules were invented by chemically altering benzodiazepines, a class of anti-anxiety and sedative drugs that also activate the GABA system.

In preclinical models of stress-induced memory loss, a single dose of the molecules was able to quickly improve symptoms with memory performance returning to normal levels in 30 minutes.

In the case of preclinical models of ageing, therapeutic molecules rapidly reversed memory declines and performance was observed to increase to 80% following administration.

The researchers said that the performance essentially reached levels seen in youth or earlier stages of adulthood, and lasted over two months with daily treatment.

These molecules were able to renew underlying brain impairments that were responsible for memory loss.

CAMH Campbell Family Mental Health Research Institute deputy director Etienne Sibille said: “The aged cells regrew to appear the same as young brain cells, showing that our novel molecules can modify the brain in addition to improving symptoms.

“We’ve shown that our molecules enter the brain, are safe, activate the target cells and reverse the cognitive deficit of memory loss.”

The molecules are expected to advance into the clinical research stage in two years. The team believes that the therapeutics have the potential to even prevent memory loss at the beginning of Alzheimer’s disease.

Findings from the research were presented at the American Association for the Advancement of Science (AAAS) Annual Meeting in Washington DC, US.

15 February 2019

Passage Bio receives $115m in funding to address CNS diseases

Gene therapy company Passage Bio has launched in the US with $115.5m series A funding to develop AAV-delivered therapies for the treatment of rare monogenic central nervous system (CNS) disorders.

The financing round was led by OrbiMed Advisors. Frazier Healthcare Partners, Versant Ventures, New Leaf Venture Partners, Vivo Capital and Lilly Asia Ventures also joined the funding round.

Passage Bio will use the funds to develop five therapeutic candidates under a research, collaboration and licence agreement with the University of Pennsylvania (Penn).

The partnership also involves Penn’s Gene Therapy Program (GTP) and the Penn Orphan Disease Center (ODC).

Lead candidates of the project include programmes for GM1 gangliosidosis (GM1) and frontotemporal dementia (FTD).

GM1 is an autosomal recessive genetic disorder, while FTD is characterised by progressive impairment of executive function, language and social interaction.

The company aims to bring these programmes into the clinic by early next year.

Passage Bio co-founder and chief scientific advisor James Wilson said: “We believe this is a truly unique partnership, which gives Passage access to certain Penn AAV technologies developed at the GTP, our strong preclinical translational science capabilities and orphan drug development know-how.

“We are confident in this team’s ability to move new treatments for rare CNS monogenic diseases through clinical development in an effort to one day provide new treatment options for patients with chronic unmet needs with high mortality.”

The company holds an option to fund the preclinical development of up to seven additional rare monogenic CNS programmes at the GTP.

In addition, Passage Bio can choose to license new intellectual property resulting from these programmes from Penn.

14 February 2019

Decoy platelets could prevent clots and cancer spread

Researchers at the Wyss Institute at Harvard University have created ‘decoy’ platelets that could potentially reduce blood clots, as well as prevent cancer from spreading.

Platelets help in the formation of blood clots to stop bleeding and promote healing.

However, abnormally activated platelets can also result in dangerous clots and cancer metastasis, among other health conditions.

Antiplatelet drugs are available to treat platelet-related disorders, but reversing the effects of these drugs is not easy and exposes patients to the risk of uncontrolled bleeding following injury.

To address such concerns, the team created a drug-free, reversible antiplatelet therapy involving deactivated decoy platelets, which were prepared by removing outer lipid membrane and inner contents of normal platelets.

The new platelets were smaller than normal ones, but with most of the adhesive proteins.

When added to microfluidic blood vessel-like channels, these cells demonstrated reduced aggregation and binding, thereby preventing the development of blood clots. The findings were found to be consistent with tests in rabbits.

Wyss Institute postdoctoral fellow Anne-Laure Papa said: “The decoys, unlike normal intact platelets, are unable to bind to the vessel wall and likely hinder the normal platelets’ ability to bind as well.”

Furthermore, adding fresh platelets to the channels allowed the researchers to reverse the decoys’ inhibition of normal platelet activity. This is expected to facilitate the reversal of the therapy effects in a small time period.

The team also tested their decoy platelets in tumours as platelets are known to protect cancer cells from the body’s immune system and in turn help them in metastasis.

When the researchers mixed normal and decoy platelets with human breast cancer cells, they were able to almost completely prevent the platelets from helping the cancer cells.

In addition, the team reported that mice administered with platelets plus decoys developed significantly smaller and fewer metastatic tumours than those injected with normal platelets.

The researchers hope that the decoys could be used along with chemotherapy to prevent tumours from spreading or injected during surgeries to stop released tumours from forming new ones in other body parts.

In addition, the decoys could be created from platelets extracted from the same patient, facilitating a form of personalised cellular therapy that would not cause an immune reaction.

Currently, the team is working on making the decoy platelets last longer in the bloodstream. They also plan to evaluate if the decoys can be used to directly deliver drugs to blood clot and tumour sites.

11 February 2019

Samsung Bioepis forms new alliance to expand in China

Samsung Bioepis has signed a licensing deal with healthcare-focused private equity firm C-Bridge Capital to accelerate expansion in mainland China.

The agreement involves the biopharmaceutical company’s SB11, SB12 and SB3 biosimilar candidates, which reference Lucentis (ranibizumab), Soliris (eculizumab) and Herceptin (trastuzumab) respectively.

Lucentis and Herceptin are Genentech products, while Soliris is part of the Alexion Pharmaceuticals portfolio.

As part of the alliance, C-Bridge will establish a biopharmaceutical firm called AffaMed Therapeutics.

The new firm will partner with Samsung Bioepis on further advancing the biosimilar candidates, including their clinical development, regulatory registration and commercialisation in China.

In turn, Samsung Bioepis will get an upfront payment and royalties on sales. Precise financial terms of the agreement have not been disclosed.

Samsung Bioepis president and CEO Christopher Hansung Ko said: “We want to play an important role in widening access to high-quality healthcare for patients throughout China.

“C-Bridge is the right partner for this mission as evidenced in its exceptional track record of successfully turning portfolio companies like AffaMed Therapeutics into leading biopharmaceutical companies in China and beyond.”

Currently, Samsung Bioepis offers four biosimilars Benepali (etanercept), Flixabi (infliximab), Imraldi (adalimumab) and Ontruzant (trastuzumab) across Europe.

The company provides Renflexis (infliximab-abda) in the US, where it also secured approval for Ontruzant (trastuzumab-dttb).

In addition, a biologics licence application for another biosimilar candidate SB5 (adalimumab) is currently being reviewed by the US Food and Drug Administration (FDA).

Established in 2012, Samsung Bioepis is a Korean joint venture between Samsung BioLogics and Biogen.

8 February 2019

Insulin delivering drug capsule could replace injections

A research team led by the Massachusetts Institute of Technology (MIT) in the US has developed a pill for oral delivery of insulin, potentially enabling type 2 diabetes patients to replace their daily injections.

In addition to MIT scientists, the team includes researchers from Brigham and Women’s Hospital and Danish pharmaceutical company Novo Nordisk.

The new drug capsule is embedded with a small needle that is made of compressed, freeze-dried insulin and injected after the pill reaches the stomach.

This insulin is produced using the same process used to form tablets of medicine, and the needle’s shaft is made of a biodegradable material.

The pill is designed to avoid entry of needles into the stomach wall, where they would be broken down by acids before having any therapeutic effect.

When tested in animals, the researchers observed that the capsule allowed delivery of enough insulin to lower blood sugar levels comparable to those achieved via injections through skin.

The researchers believe that the pill can be used to deliver other protein drugs.

MIT Koch Institute for Integrative Cancer Research member Robert Langer said: “We are really hopeful that this new type of capsule could someday help diabetic patients and perhaps anyone who requires therapies that can now only be given by injection or infusion.”

In the insulin delivering drug capsule, the needle is connected to a compressed spring that is held by a disk of sugar.

After the pill reaches the stomach, water in the organ dissolves the sugar disk, releasing the spring and injecting the needle into the stomach wall.

The team hopes that the lack of pain receptors in the stomach will avoid any feeling of injection. They claim their design ensures that the capsule can orient itself to enable the needle’s contact with the stomach lining.

Furthermore, the researchers said that the dissolution rate of the insulin can be controlled when the pill is prepared.

MIT graduate student and study first author Alex Abramson said: “What’s important is that we have the needle in contact with the tissue when it is injected. Also, if a person were to move around or the stomach were to growl, the device would not move from its preferred orientation.”

In pigs, the researchers were able to deliver 300 micrograms of insulin, and could increase it to the 5 milligrams usually needed by a type 2 diabetes patient.

Once the capsule contents were released, it passed through the digestive system, and did not lead to any adverse effects during the study.

Currently, the MIT researchers are working with Novo Nordisk to advance the technology and manufacturing process for the insulin delivering drug capsule.

7 February 2019

Fate Therapeutics’ stem cell therapy cleared for IND application

Fate Therapeutics has announced the US Food and Drug Administration (FDA) has allowed it to begin clinical investigation and submit an investigational new drug (IND) application for its cell therapy FT516.

Three weekly doses of FT516 will be studied either alone or in combination for safety and tolerability for three relapsed haematologic malignancy indications. It will be tested in acute myelogenous leukaemia as a monotherapy, non-Hodgkin’s lymphoma in combination with rituximab and for multiple myeloma in combination with elotuzumab, plus pomalidomide and dexamethasone.

FT516 is an off-the-shelf NK cancer cell immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) engineered to express a novel CD16 Fc receptor.

Fate Therapeutics’ president and CEO Scott Wolchko said: “Our industry-leading iPSC product platform enables the manufacture of engineered cell products that can be extensively characterised, cryopreserved and delivered ‘on demand’ to reach more patients.

“FT516 is a first-of-kind cell product in that it originates from a single genetically engineered pluripotent stem cell, which serves as a clonal master cell line that can be repeatedly used to mass-produce large quantities of homogeneous cell product in a cost-effective manner.

“This innovative approach uniquely supports a new treatment paradigm with engineered cell therapies, where multiple doses of cell product are readily available for administration with the goal of driving deeper and more durable responses.

“We look forward to treating patients with multiple doses of FT516, including in combination with FDA-approved monoclonal antibody therapy, across multiple treatment cycles in this first clinical study.”

CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity (ADCC), the underlying mechanism of monoclonal antibodies’ clinical efficacy in treating various cancers.

FT516 incorporates a new CD16 Fc receptor modified to enhance ADCC through preventing down-regulation and improving binding to tumour-targeting antibodies.

This is Fate Therapeutics’ second off-the-shelf iPSC-derived NK cell product cleared for clinical investigation by the FDA. In November 2018, FT500 was cleared for clinical investigation for use in combination with checkpoint blockade therapy to treat solid tumours.

7 February 2019

FDA approves Sanofi’s Cablivi as first therapy for rare blood disorder

The US Food and Drug Administration (FDA) has approved Sanofi’s Cablivi (caplacizumab-yhdp) to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood clotting disorder.

Cablivi is a nanobody-based drug designed to target the von Willebrand factor (vWF) protein associated with blood haemostasis. It prevents the protein’s interaction with platelets to inhibit formation of blood clots.

The drug was developed by Belgian pharmaceutical firm Ablynx, which was acquired by Sanofi last year.

It is Sanofi’s first nanobody-based medicine and the first FDA-approved therapy specifically indicated to treat aTTP. The indication covers use of the drug along with plasma exchange and immunosuppressive therapy.

aTTP is a life-threatening autoimmune blood disorder characterised by extensive blood clots in the small blood vessels throughout the body. The clots hinder oxygen and blood supply to the major organs, resulting in strokes, heart attacks, brain damage or death.

Commonly, patients have to undergo daily plasma exchange, which involves use of a machine that extracts blood from the body, mixes with donated plasma and returns it to the body.

The FDA noted that use of this therapy in combination with immunosuppressive drugs for days or even weeks could still lead to diseases recurrence.

FDA Oncology Center of Excellence director Richard Pazdur said: “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

The regulatory agency’s approval is based on data obtained during the pivotal Phase III HERCULES clinical trial conducted in 145 adults experiencing an aTTP episode.

During the trial, combination of Cablivi with plasma exchange and immunosuppressive therapy was compared to placebo, plasma exchange and immunosuppressive therapy combination.

Results showed significantly shorter time to platelet count response with the drug combination.

The drug also demonstrated decrease on a composite endpoint of aTTP-related death, disease recurrence or a major thromboembolic event.

However, Cablivi comes with a warning about the risk of severe bleeding.

The drug is set to be commercially launched in the US by the end of the first quarter of this year, with a list price of $270,000.

6 February 2019

Researchers launch virtual library of docked molecules for drug discovery

Researchers from the University of North Carolina and the University of California San Francisco have launched a library of molecules that have been structurally attached to receptors through computer simulation to aid drug discovery.

The team expects the library to grow to more than one billion molecules by 2020 and could increase the number of compounds currently ready for use in drug discovery significantly.

The docking library will be funded by the US National Institutes of Health (NIH), including the National Institute of Mental Health (NIMH), National Institute of General Medical Sciences (NIGMS), the NIH Common Fund, and National Institute of Neurological Disorders and Stroke (NINDS).

The library is based on studies conducted by the researchers. One of these studies involved testing a virtual structure-based docking approach on an antipsychotic drug and LSD, and led to the creation of a novel painkiller, which targets brain analgesic circuitry without the side effects of morphine.

A second study investigated 138 million molecules that could attach to a D4 receptor linked with dopamine or to enzyme AmpC related to antimicrobial resistance. The researchers synthesised and tested the top 549 resulting molecules that docked best with the D4 receptor and the 44 that attached best with enzyme AmpC.

This unveiled new drug-like molecules that could successfully bind to and target the D4 receptor, rather than the similar D2 or D3 receptors, and to the enzyme.

The researchers demonstrated that a larger library can improve accuracy in identification of false positive molecules by applying computer simulations to 130 reactions from 70,000 building block molecules. As more molecules were added to the library, the ratio of true molecules to false positives improved.

NIMH director Joshua Gordon said: “This new study illustrates the potential of unbiased computational screening and molecular docking to discover new tool molecules and potential therapeutic agents, providing a rapid and robust pathway that will lead directly to novel drug treatments for mental illnesses.

“Only those relatively few candidate molecules that best match the target profile on the computer need to be physically made and tested in a wet lab.”

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