The Snippet: Weaponized antibodies use new tricks to fight cancer

Efforts to develop antibodies that can ferry drugs into cancer cells and minimize damage to healthy tissue are gathering steam. The next generation of these ‘weaponized antibody’ therapies, called antibody–drug conjugates (ADCs), is working its way through clinical trials. The concept that underlies these drugs is simple, as they re-purpose an antibody as a vehicle to deliver a toxic drug into a cancer cell. When the antibody in an ADC seeks out and docks onto a tumour cell, the cell takes it up and cleaves the molecular links that bind the drug to the antibody. This frees the drug to kill the cell from within. Researchers have been chasing ADCs for decades. The US Food and Drug Administration has approved three, but one was subsequently withdrawn from the market amid concerns that it was not effective and posed safety risks. The other two have met a happier fate: sales of Adcetris (brentuximab vedotin), approved in 2011 to treat lymphoma, and Kadcyla (trastuzumab emtansine), approved in 2013 to treat breast cancer, have been encouraging.

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EC grants marketing authorisation for Takeda’s Ninlaro capsules

The European Commission (EC) has granted conditional marketing authorisation for Takeda Pharmaceutical’s Ninlaro capsules. The oral proteasome inhibitor is indicated in combination with lenalidomide and dexamethasone for adult patients with multiple myeloma who have previously received at least one therapy. The EC’s decision was based on data from the pivotal Phase III Tourmaline-MM1 trial, which showed that the capsule with lenalidomide and dexamethasone increased the length of progression-free survival by about 40% in patients with relapsed and refractory multiple myeloma.

Pfizer cuts €400M plant expansion after dumping cholesterol-lowering drug program

Pfizer is dumping much of the €400 million plant expansion in Ireland it was planning to support it. With the decision not to proceed with the pro-protein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) bococizumab, the New York drug maker will not need the 371,300-square-foot expansion of its Grange Castle biologics manufacturing unit or the 300 or so jobs that would have brought. Following the decision to discontinue the development of bococizumab, part of the potential expansion for which the planning permission was sought will not go ahead. Expansion in relation to other incoming products will continue as planned, involving investment, recruitment and new technology.

Drug regulation: 27 medicines sold by top firms ‘fail’ quality tests

In a major crackdown since March this year, drug regulators of seven states have alleged that 27 medicines — sold by 18 major drug companies in India — are of “substandard” quality, citing grounds such as false labelling, wrong quantity of ingredients, discoloration, moisture formation, failing dissolution test and failing disintegration test. Some of the key brands which were alleged to be substandard are: antipsychotic drug Stemetil and antibiotic drug Pentids from Abbott India; anti-bacterial medicine Althrocin by Alembic Pharma; migraine medication Vasograin by Cadila Pharma; popular cough syrup Ascoril by Glenmark Pharma; worm infection drug Zentel by GSK India; arthritis medication Hydroxychloroquine (HCQS) by Ipca Labs; anti-inflammatory medication Myoril by Sanofi Synthelabo; and Torrent Pharma’s hypertension drug Dilzem.

Merck’s Keytruda nabs FDA’s ‘priority’ tag in microsatellite instability-high cancer

The immuno-oncology med has taken the spotlight back with a priority review tag from the FDA. Merck’s Keytruda isn’t letting rival Opdivo from Bristol-Myers Squibb soak up all the November regulatory attention. The agency doled out the distinction to Keytruda for the treatment of previously treated patients with advanced microsatellite instability-high cancer, the New Jersey pharma giant said on Monday, and it should speed the med’s path down the regulatory pathway. If Keytruda ultimately snags an approval, Merck will add it to the list of indications its budding star already boasts in melanoma, non-small cell lung cancer and head-and-neck cancer. Microsatellite instability-high cancer is an area where Merck’s competitors haven’t yet hit the market, meaning it’s an opportunity to build a lead.

Vasomotor Symptoms of Menopause-Emerging Therapies

Vasomotor symptoms occur when a woman reaches the state of menopause and the ovaries stop producing eggs, resulting in the reduction of secretion of hormones such as estrogen and progesterone. Therapies available for vasomotor symptoms of menopause are hormonal and non-hormonal, where hormone therapy is the most effective therapy for hot flashes. Several hormone therapies such as Duaveetm (conjugated estrogens/bazedoxifene), EvaMist and Minivelle (Estradiol Transdermal System) are already approved for the treatment of vasomotor symptoms of menopause. Non-hormonal therapies for vasomotor symptoms of menopause include Paroxetine, which has been used for many years in case of depression but can be taken at a lower dose for hot flushes.

Pipeline of vasomotor symptoms of menopause include ESN-364, NT 814 and MLE4901 that targets the Neurokinin 3 Receptor. Estrogen receptor is also an important target for several companies such as TherapeuticsMD, Radius Health, Inc., Mithra Pharmaceuticals etc. EndoCeutics, Inc and TherapeuticsMD, Inc are developing the fixed dose combination product, which are in phase III stage of development. EndoCeutics’s therapeutic candidate, (Acolbifene+Prasterone) a combination product, targets the estrogen receptor modulator (SERM), and has shown positive results in several clinical studies performed in healthy postmenopausal women and in women with advanced breast cancer.

TheapeuticsMD’s fixed dose novel combination product (Estradiol + Progesterone), which is also known as TX-001HR is being developed under 505(b) (2) regulatory pathway. The company is anticipating topline results in the fourth quarter of 2016 for the ongoing Replenish Trial. If the drug is approved, it would be the first and only FDA-approved bio-identical combination of estradiol and progesterone for treatment of moderate-to-severe vasomotor symptoms due to menopause.

Several other companies like Euroscreen, NeRRe, Millendo etc. have also raised funding from the different ventures for their clinical development. Various major and minor pharmaceutical companies are working relentlessly to improve the vasomotor symptoms in women. So, one can say that promising therapies are emerging and will supersede the unmet need of disease.

Insight by:
Sukhvinder Singh
Associate Analyst

High Risk Smoldering Multiple Myeloma

Smoldering Multiple Myeloma (SMM) is an asymptomatic condition, and this concept was first described by Kyle and Greipp in 1980. They described the entity as an intermediate stage between monoclonal gammopathy of undermined significance (MGUS) and multiple myeloma (MM) on the basis of their research. The typical age of diagnosis is recorded as 50 to 70 years. As this condition is asymptomatic, the newly diagnosed patients are typically diagnosed when an M protein is discovered on laboratory testing as part of the workup of a variety of disorders.

For a SMM patient at high risk, there is 50-79% of progression risk for MM or related disorder in the first 2 years. Biomarkers such as clonal plasma cell bone marrow infiltration ≥10%, serum M-protein ≥3 g/dL and/or Serum-free light chain ratio > 0.125 or <8 are clear cut indicator of higher risk.

The worldwide population of HRSMM is expected to increase at a remarkable rate in future. Among all major markets, United States is expected to have highest number of HRSMM population, growing at a higher rate, followed by other market. Based on studies and analyses, the total HRSMM population is expected to rise in certain markets and fall in other as well, in coming years.

At present, there’s no drug approved for the treatment of HRSMM. The treatment of patients with high-risk cytogenetic factors remains an area of unmet medical need mainly due to the unavailability of the specific treatment, and loopholes in the diagnosis. Misdiagnosis and delayed diagnosis is also one of the challenges in the treatment of HRSMM and improvement in the diagnostics might prove to be an important life saving effort.

Insight By:
Mohammad Rizwan
Associate Analyst


NgAgo gene-editing, claiming to be a better alternative to CRISPR gene editing, falls into a controversy in peer-reviewed papers

Six months ago, Chinese researchers reported that an enzyme called NgAgo could be used to edit mammalian genes – and that it might be more accurate and more versatile than the popular CRISPR-Cas9 gene-editing technique. But almost immediately, other scientists complained on internet forums that they could not replicate the experiment. Now, a paper with 20 authors, published in Protein & Cell, lists multiple attempts that failed to replicate the original experiment – while another, published in Cell Research, suggests that NgAgo may only block, but not edit, genes when it is injected into zebrafish (Danio rerio) embryos. The debacle has raised questions about a 224-million yuan (US$32-million) gene-editing centre that Hebei University of Science and Technology announced that it would build, to be paid for with local government money.

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Novartis Buys Blood Disease Drug Maker for $665mn

Novartis has acquired Selexys Pharmaceuticals, a drug maker specializing in development of therapeutics in certain hematologic and inflammatory disorders. Novartis exercised its right to acquire Selexys following receipt of results of the SUSTAIN study, a Phase II trial evaluating the use of SelG1, an anti-P-selectin antibody, in the reduction of vaso-occlusive pain crises in patients with sickle cell disease (SCD). Terms of the deal could total up to $665 million in upfront, acquisition and milestone payments.

US FDA approves Intrarosa to treat dyspareunia

The US Food and Drug Administration (FDA) has approved Intrarosa (prasterone) to treat women experiencing moderate-to-severe pain during sexual intercourse (dyspareunia). Dyspareunia is a symptom of vulvar and vaginal atrophy (VVA) caused by the menopause. It is marketed by Canadian company Endoceutics. Levels of oestrogen during menopause decline in vaginal tissues and may cause a condition known as VVA, leading to symptoms such as pain during intercourse.

Mayne Pharma Launches Temozolomide Capsules in U.S.

Mayne Pharma has launched temozolomide capsules in the U.S. in 5mg, 20mg, 100mg, 140mg, 180mg and 250mg doses. The generic version of branded Temodar, temozolomide capsules are indicated for the treatment of adult patients with newly diagnosed cancerous brain tumors known as glioblastoma multiform concomitantly with radiotherapy and then as maintenance treatment. Mayne Pharma will distribute the drug on behalf of its partner, IDT Australia, which developed the product and is manufacturing the product.

Oxford Genetics Receives Grant to Create Virus Packaging Cell Lines

Oxford Genetics, which develops DNA systems and bioproduction solutions, will work in collaboration with the University of Oxford to generate cell lines for the scalable manufacture of retrovirus and lentivirus vectors. The $1 million program will see the provider of synthetic biology solutions use its newly acquired facilities at the Oxford Science Park to extend its product and service offering into the virus manufacturing space. The program will span 12 months and follows the recent announcements from Oxford Genetics that is has expanded its board to include several industry experts, acquired new state-of-the-art cell line development facilities, and received £2 million investment from Mercia Technologies PLC.

Idiopathic Pulmonary Fibrosis: Recent Scenario

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology, closely associated with interstitial lung disease that shows similar symptoms but with different mode of action. The disease is known so because it primarily involves the interstitium, where scars develop and progresses towards the center of the lungs, making breathing difficult for the patient. It develops primarily in older adults, and is sometimes associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia.

There is currently no drug especially for IPF, and no procedures or medications that can remove the scarring from the lungs. Treatments are used to slow progression of the lung scarring, and may not necessarily lessen the symptoms of cough and breathlessness. Pirfenidone and Nintedanib have both been shown to slow the progression of IPF; however, some patients cannot take these medications due to their side effects.

On the basis of above mentioned circumstances, researchers are coming forward for the discovery of more and more drugs. Drug pipeline of this disease has 58 active drugs; however, it will take some time to see them launched into the market. Only one drug is available commercially, and that is Thrombomodulin Alfa (ART-123). It is a Phase III drug of Asahi Kasei Pharma Corporation, already marketed in Japan under the name of Recomodulin for the treatment of disseminated intravascular coagulation (DIC). 14 drugs are in Phase II; whereas the preclinical and discovery stage has approximately 30 drugs. It can be said that the road to a better treatment of IPF is a long one, with many drugs on the way to reach the stage of becoming a treatment option for IPF patients.

The Business Cocktail

Novartis eyes $8B Amneal buy

Novartis is weighing a deal for the generics maker Amneal Pharmaceuticals to expand its already-hefty Sandoz unit, at a time when two of its biggest rivals in the field are integrating big buyouts of their own. The Amneal buy could be worth up to $8 billion. Joerg Reinhardt, chairman of the Swiss drug maker, made the broadest suggestion yet that Alcon’s days under Novartis’ umbrella are numbered. The ophthalmology unit has been struggling in recent quarters, and Reinhardt suggested that Alcon needs to recover soon, or face life under new ownership.

Pfizer considers cashing in on its consumer health business

Rumour mills are going abuzz with the news that Pfizer is considering doing something with its consumer health operations and that it could bring in around $14 billion. However, there is no indication whether Pfizer is thinking of a sale, or a tax-free spinoff like it used for its animal health unit Zoetis, or some kind of an asset swap.

Mylan pushes to seal $465M settlement as it posts a Q3 loss

Mylan executives are working to finalize a $465 million settlement with the federal government for Medicaid overcharges. The deal would see Mylan admit no responsibility but resolve allegations that the company misclassified its big-selling epinephrine injector as a generic. CEO Heather Bresch told analysts on Wednesday that the company is looking for bolt-on deals rather than a big acquisition.

Valeant in talk with Takeda for $10B Salix deal

The Canadian pharma is in advanced talks to sell its Salix gastrointestinal unit to Takeda for about $10 billion. Valeant had acquired Salix just a year and a half ago for about $11 billion, beating out interested suitors Shire and Endo. Meanwhile, the deal-talks news put Valeant shares on the rise just after word of the accounting fraud sent them to their lowest depths since 2010.

Phosphoinositide 3-Kinase (PI3k) Inhibitors: Emerging target therapies against Cancer

Phosphoinositide 3-kinases (PI3Ks) were discovered in 1980, and since then drug developers have accelerated their research funds in order to find potential drug candidate for inhibiting PI3Ks for the treatment of cancers. Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that act as intermediate signaling molecules in PI3K/AKT/mTOR signaling pathway. They are the key molecules that play central role in regulation of several cellular processes such as proliferation, adhesion, survival, and motility.

Mutation in these genes causes dysregulation of PI3K, which causes resistance to conventional therapies including biologics, hormonal therapy, tyrosine kinase inhibitors, radiation, and cytotoxics in breast cancer, glioblastoma, and non-small cell lung cancer. Latest research led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) demonstrates that “PI3K is a master regulator integrating a cancer cell’s architecture and its metabolism”. The study infers that cancer cells highly rely on the metabolism of sugar for their self-renewal as it not only generates energy but also biomass and PI3K inhibitors can inhibit the glucose breakdown.

Over the last 26 years, PI3K has been one of the most attractive molecular targets for cancer. Idelalisib is the first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin’s lymphoma and relapsed small lymphocytic lymphoma. There are many drugs in pipeline such as TGR-1202, Alpelisib, Taselisib etc. that are in highest stage of clinical development. Several leading drug developers such as GlaxoSmithKline, Novartis, Bayer, and Pfizer have progressed their lead compounds in clinical trials. More than 35 drugs are in different stages of drug development for different isoforms of PI3Ks.

Insight by:
Jyoti Kumari
Associate Analyst