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The launch of Novartis’ Beovu ophthalmology drug could be compromised after a safety warning from doctors over several cases of sight-threatening inflammation of blood vessels.

Beovu (brolucizumab) is a follow-up to the company’s blockbuster Lucentis (ranibizumab) and is approved for wet age-related macular degeneration (AMD).

It offers a less frequent dosing schedule, after an initial loading phase, and Novartishopes it will appeal to doctors as this means cost per patient is lower compared with Lucentis and Bayer/Regeneron’s rival, Eylea (aflibercept).

But there are concerns that doctors will put off prescribing Beovu following a warning from the American Society of Retina Specialists (ASRS) issued over the weekend.

The ASRS noted that since approval on 7th October last year there have been 14 cases of vasculitis – inflammation of the blood vessels – with 11 reported to be occlusive retinal vasculitis, a sight-threatening condition.

Novartis’ shares were down as much as 5.5% on Monday afternoon as the announcement spooked investors.

Analyst Peter Welford from Jefferies noted that so far around 46,000 Beovu injections have been administered in the US, and that a Novartis safety committee is reviewing the cases.

Jefferies had been forecasting peak global sales of $2.5 billion, but this could be halved because of a slower launch, hitting earnings per share by up to 2% or 2.5 Swiss francs ($2.56), according to Welford.

A “worst case scenario” where Beovu is withdrawn from the market cuts earnings per share by 4% and would add to Novartis’ woes following the phase 3 trial failure of fevipiprant for asthma.

A clinical trial of an intrathecal formulation of spinal muscular atrophy gene therapy Zolgensma has also been put on hold, leaving Novartis in need of “positive pipeline news”, said Welford.

In a note Welford said: “These safety concerns are likely to dampen retina physicians’ initial uptake of Beovu, in our view, with many perhaps now waiting until their initial switched patients have received more injections of the drug before re-considering wider adoption.”

Jefferies’ own review of the FDA Adverse Event Reporting System database suggests a higher incidence of vasculitis, blindness and eye inflammation on Beovu since launch compared with either Eylea or Lucentis, although these reports have not undergone review.

The system recorded a spike in intraocular inflammation of Eylea in February 2018 but these concerns proved largely unfounded.

One potential cause is intraocular inflammation before administration – a contraindication on the drug’s label, and Welford added that a similar proportion of patients lost vision from baseline versus Eylea in trials so far.

There were five cases of retinal occlusive vasculitis after around 58,000 doses on trials, said Welford.

The FDA has approved Lundbeck’s eptinezumab prophylactic treatment for migraine, the last from a gang of four drugs from a new class.

Teva, Eli Lilly, and Amgen/Novartis already have calcitonin gene-related peptide (CGRP) class migraine drugs on the market, but Lundbeck is hoping to differentiate itself from the competition with an intravenous formulation taken in a clinic instead of self-injected with a pen.

Allergan also has an oral CGRP drug, Ubrelvy (ubrogepant) approved in migraine.

These drugs are not taken to relieve symptoms: they are taken at regular intervals after clinical trial data showed they help to reduce frequency of migraine episodes.

While patients may not consider the IV formulation to be as convenient as its rivals, it could mean that more of the costs are covered by the US health system.

Lundbeck also noted that the treatment benefit with eptinezumab, branded as Vyepti was seen as early as one day after infusion.

The Danish pharma hopes that this early onset of efficacy will also help the drug to compete in a highly competitive market.

A spokesperson for Lundbeck told pharmaphorum in an email that the price for Vyepti will be announced on Wednesday.

The spokesperson added: “Our research shows that patients care about relief and getting it fast, not about how the drug is delivered.

“Also, the relevant patients are already seeing their physician once a quarter, so the quarterly infusion can be rather convenient.”

Eli Lilly and Novartis’ CGRP drugs are taken monthly, while Teva’s drug can be taken quarterly.

The recommended dose is 100 mg every three months, while some patients may benefit from a dose of 300 mg.

Lundbeck did not provide any sales forecasts for Vyepti, but said that it has “blockbuster potential”.

This tallies with the price Lundbeck paid for the drug’s original developer, Alder BioPharmaceuticals late last year.

Lundbeck paid $18 per share up front, plus $2 a share tied to approval of Vyepti in Europe, valuing Alder at $1.95 billion in total.

The non-invasive eye scan utilises the device to find a pattern of subtle electrical signals in the retina that are different in children on the autism spectrum, which are directly linked to differences in their brain development.

The scan was tested on around 180 people with and without autism between the ages of five and 21 in collaboration with Yale University in the US, University College London and Great Ormond Street Hospital in the UK, as part of a study published in the Journal of Autism and Developmental Disorders.

These potential biomarkers for autism spectrum disorder (ASD) could allow for early detection of other disorders, such as attention deficit hyperactivity disorder (ADHD).

Dr Paul Constable, a senior lecturer at the College of Nursing and Health Sciences at Flinders University, has been searching for an autism “biomarker” since 2006, in an effort to improve early detection and intervention methods after his own child was diagnosed.

He said: “The retina is an extension of the brain, made of neural tissue and connected to the brain by the optic nerve, so it was an ideal place to look.

“The test is a quick, non-intrusive eye-scan using a hand-held device and we anticipate it will be equally effective on younger children. Very early diagnosis means not only can children receive important interventions, but families are empowered to get the necessary supports in place, come to terms with the diagnosis, and make informed decisions.”

Dr Constable’s research team is also investigating the scan to detect autism in younger children and other conditions including attention deficit hyperactivity disorder, and other neurodevelopmental disorders.

He added: “Now we have found a likely candidate biomarker for autism, the next stage is to look at young children, even infants, as the earlier we can get to intervention stages the better.

“Very early diagnosis means not only can children receive important interventions, but families are empowered to get the necessary supports in place, come to terms with the diagnosis, and make informed decisions.”

Ian Bolland asks EJ Shin, Jenax and Andy Baker, HP1 Technologies, about the effect flexible batteries could have on medical devices.

This interview followed a webinar on how flexible batteries can be used in the manufacturing process, ‘creating product innovation breakthroughs with flexible power.’ It covered the importance of continuous innovation, changing the mindset of what batteries can do, and new standards of safety, flexibility and control.

According to MarketsandMarkets the flexible battery market is estimated to grow from $97 million in 2016 to $958 million by 2022, propelled by the miniaturisation of electronics devices, and the demand for wearables.

Shin notes that wearables can benefit from flexible batteries. There is also a use within clinical setting, allowing medical professionals to manoeuvre easily instead of carrying power banks.

Shin adds: “Flexible batteries can be an enabling technology for many devices and for many aspects in the medical field.”

So where is the opportunity within medical device design? Is the demand for flexible batteries being driven by device design, or are the batteries leading to more innovative designs?

“I would say it’s the synergy of both,” Shin explains. “Device makers want to make the device more flexible so flexible components are needed. We want to find a perfect or usable application that can be benefitted by flexible batteries.”

The batteries were also shown to have a life comparable to standard batteries, while also showing that when they have been cut through, there is no sign of leakage – a potential selling point when it comes to being used in a field when safety is imperative.

“Making the flexible battery is one technology and also making the entire battery safe is another. We combine the two. We have made it safe by developing semi-solid electrolytes and also years of testing and experience on production know-how.”

Last year Jenax, announced a breakthrough in battery safety with non-flammable liquid electrolytes. This aims to solve the problem of batteries that catch fire or explode in extremely hot temperatures or when short circuited. This technology can increase the safety of wearables.

Andy Baker, CEO – sport and leisure – HP1 Technologies, which builds printable graphene-based sensor systems, developed a helmet containing over 20 sensors on the surface.

Baker recently attended an NFL conference. The reduction in concussion in the sport is a key issue. The helmet requires sensors, so needs flexible batteries.

He explains that connectivity is a huge consideration but it’s possible to include flexible batteries in devices such as smart bandages; and suggests there is room for diversification as well as highlighting safety features.

“The main area for health is they do not explode when pierced or leak corrosive substances. Flexible batteries can be pierced and cut and will still supply power until replaced and will only leak a small amount of a polymer gel which is harmless and can be on the skin without causes any discomfort or burns.

“I think the main message is to think differently, if you think differently you can power differently.”

A non-invasive blood test which can detect all cancers at every stage with high accuracy is to launch in the UK.

Cancer diagnostics, treatment and prevention experts RMDM has developed PanTum Detect. It can detect any cancer at any stage of its growth with a 99.05% specificity and 97.5% sensitivity. This technology is already on the market in other parts of the world, including in Holland and Germany.

Dr Ahmed Bourghida, chief scientific officer at RMDM, said: “Following extensive research, investment and development, we are now in a position to revolutionise cancer care in the UK. Early detection of cancer is absolutely vital when it comes to improving cancer outcomes and saving lives, and our unique, non-invasive blood test will take away the fear factor that many people feel around biopsies, giving the NHS the confidence to run more universal screening campaigns.”

The technology has been tested and validated in the UK at the Centre for Health and Human Performance (CHHP) at 76 Harley Street in London.

As one in two people in the UK will develop cancer during their lifetime, there is an urgent need for better diagnosis. Screening programmes in the UK remain limited and out of 200 types of cancers, the UK currently provides screening services for just three.

Elizabeth Moore, managing director at the Centre for Health and Human Performance, said: “Myself and the team at CHHP are absolutely thrilled to be involved in the revolutionary launch of the PanTum blood test, an innovation in cancer blood testing. CHHP has been involved in the long process of trialling and testing for many months in order to validate the test, which is now ready for the UK market.

“The PanTum test has emerged as a unique test to the UK market, with minimal invasion and can screen for cancer before it is too late. The blood test is a significant breakthrough in proactive medical management that will enable patients and doctors alike to detect much earlier change in metabolism that differentiate cancer cells from normal cells at such an early stage. We look forward to seeing how the development of this test within the UK can grow to a nationwide service.”

The U.S. Food and Drug Administration (FDA) agreed to review BioMarin Pharmaceutical’s Biologics License Application (BLA) for valoctocogene roxaparvovec (valrox) for adults with hemophilia A. It was accepted for Priority Review. The target action date is August 21, 2020.

Valrox is a gene therapy to treat hemophilia A. Hemophilia A is a genetic deficiency in clotting factor VIII, resulting in increased bleeding. At this point, patients with hemophilia A are treated with Factor VIII, a protein that is infused two to three times a week. It doesn’t prevent patients from all bleeding events.

Valrox is a potential gene therapy that is administered as a single infusion. The application is built on a Phase III interim analysis of patients receiving an investigational product manufactured by the to-be-commercialized process as well as three-year Phase I/II data, which was published in January in The New England Journal of Medicine.

In addition to the acceptance of the BLA, the FDA has accepted the premarket approval application for an AAV5 total antibody assay planned as a companion diagnostic for valrox. BioMarin estimates that about 80% of people with hemophilia A in the U.S. do not have a preexisting immunity to AAV5 that would make them ineligible for this gene therapy. The test is manufactured by ARUP Laboratories, a national reference laboratory that is a nonprofit enterprise of the University of Utah and its Department of Pathology.

AAV5 is a strain of adeno-associated virus (AAV) that is designed for use in gene therapies because of its relatively low immune reaction.

“Valoctocogene roxaparvovec has the potential to be the first gene therapy approved in any type of hemophilia and the acceptance of this application and its priority review status marks a significant milestone for gene therapies in general and for the hemophilia community specifically,” said Hank Fuchs, president, Global Research and Development at BioMarin. “We recognize the decades of scientific research that has allowed us to reach this stage of development. As pioneers in gene therapy, we are proud of the medical and technological innovation represented in valoctocogene roxaparvovec, which is possible because of the scientists who did the early research, clinical investigators, the hemophilia community and the people who work here. We look forward to working with the FDA to bring this groundbreaking therapy to people with hemophilia A.”

The Phase III trial data indicated that seven out of 16 patients in the trial reached or exceeded the Factor VIII levels that U.S. and European regulators want to see. After the data cutoff period, another patient also hit the mark. The trial is still enrolling patients, so BioMarin hopes that valrox will prove it is superior to Factor VIII replacement therapy.

Reportedly, if approved, BioMarin is considering a price range of $2 million to $3 million for the therapy. Although that seems staggeringly high, even more expensive than Novartis’ Zolgensma for spinal muscular atrophy (SMA), which runs $2.125 million, BioMarin and drug pricing experts note that the current price of blood clotting treatments over the lifetime of a patient is around $25 million per patient. The therapy could potentially save the healthcare system and insurers more than $20 million over the patient’s lifetime.

But first it has to get approved and although it sounds promising, analysts and experts are debating the likelihood, noting that the regulatory agencies’ Factor VIII levels required for approval are not completely clear. And although the therapy’s efficacy and safety data were positive, there are some concerns over the duration of response, with some physicians suggesting that it will begin to lose clinical benefit if the Factor VIII levels don’t hit a plateau.

Shares of Pennsylvania-based Baudax Bio are up more than 40% in premarket trading after the company announced its pain medication Anjeso was greenlit by the U.S. Food and Drug Administration.

Late Thursday, the company said the FDA approved its New Drug Application for Anjeso (meloxicam injection), which is indicated for the management of moderate to severe pain, alone or in combination with other non-NSAID analgesics. The approval marks the first once-per-day 24-hour, intravenous COX-2 preferential NSAID, the company said. Baudax plans to launch the medications in the spring of this year.

Baudax Bio officially launched in November of last year as a spinout from Recro Pharma, Inc. The company launched with a pipeline that includes meloxicam and two neuromuscular blocking agents and a reversal agent for use in a surgical setting. In its pipeline, the company also has intranasal dexmedetomidine (Dex-IN), a non-opioid alpha-2 adrenergic agonist being developed for possible uses in pain or sedation.

Before Anjeso was approved, Baudax, when it was still part of Recro, had to address a Complete Response Letter the FDA issued last year. The company submitted a response package that answered concerns raised about Anjeso.

Gerri Henwood, president and chief executive officer of Baudax, said the approval is a major advancement in the “treatment landscape for managing moderate to severe pain,” particularly as the nation continues to battle the opioid crisis. With Anjeso, Henwood said Baudax is “thrilled” to provide a non-opioid therapeutic option that has the “potential to meaningfully impact the acute pain treatment paradigm.”

The active ingredient in Anjeso, meloxicam, is a long-acting, preferential COX-2 inhibitor that possesses analgesic, anti-inflammatory and antipyretic activities, which are believed to be related to the inhibition of cyclooxygenase type 2 pathway (COX-2) and subsequent reduction in prostaglandin biosynthesis. Approval of the drug was supported by data from three Phase III studies. Each of the studies tested Anjeso in patients who underwent different types of surgeries, including hip and knee replacements, as well as abdominoplasty and bunionectomy procedures. The trials showed Anjeso significantly reduced pain in these patients compared to placebo.

Trial data showed the medication is safe, with adverse reactions occurring in approximately 2% of patients. The most common reactions included constipation, an increase in the liver enzyme gamma-glutamyl transferase and anemia.

“The safety and efficacy of Anjeso have been well-established through several mid- and late-stage clinical studies,” Stewart McCallum, chief medical officer of Baudax Bio said in a statement. “Moreover, data from our Phase III safety trial demonstrated that Anjeso is well tolerated and impacted opioid consumption compared to placebo, further highlighting its value to patients, providers and health systems.”

IBM announced its data-driven tool, IBM Study Advance that optimizes clinical trial protocol design by providing access to real-world patient population data, a collaborative workplace and standardizing protocol template guidance.

– IBM Study Advance’s collaborative workspace is designed to allow near real-time collaboration with study design team members who can manage and assign the team to specific sections of the protocol. 

IBM Watson Health today unveiled its newest cloud-based technology IBM Study Advance at the 11th Annual Summit for Clinical Ops Executives (SCOPE).  The data-driven, study design tool, is designed to optimize clinical trial protocol design by merging automated access to real-world patient population data, standardizing protocol template guidance and providing a collaborative workspace designed to facilitate efficiency.

Collaborative Authoring to Enhance Development and Commercial Success

On average, a single protocol amendment to a Phase III clinical trial can result in approximately $500,000 (USD) in unplanned expenses and an additional 61 days to the project timeline. IBM Study Advance is designed to offer critical insights during the process of study design to help reduce the number of amendments during clinical trials. The tool is designed with an interface to provide access to commercial and claims data from de-identified patient profiles covering 89 million lives from multiple employer-sponsored U.S. healthcare beneficiaries, as well as tools to assess the impact of inclusion and exclusion criteria on the eligible patient population.

“Currently, 80% of trials experience delays in recruiting and one out of four amendments were considered completely avoidable,” said Rob DiCicco, PharmD, Deputy Chief Health Officer, IBM Watson Health. “Breakdowns in the clinical trial process, including issues caused by study design decisions, may potentially delay access to life-changing therapies for patients. IBM Study Advance aims to remove the barriers in clinical development to help researchers efficiently bring necessary therapies to patients.”

Real-Time Collaboration

Study Advance’s collaborative workspace is designed to allow near real-time collaboration with study design team members who can manage and assign the team to specific sections of the protocol.  The workspace is also designed to provide access to standard protocol templates and version control capabilities with complete traceability back to changes, aiming to reduce the average time required to author a clinical trial protocol.

Audentes Therapeutics, an Astellas company, announced it is building a gene therapy manufacturing plant in Sanford, North Carolina.

The company is investing $109 million in a new 135,000-square-feet facility, with the initial phase to take place over about 18 months. It is planned to go into operation in 2021. It is expected to create more than 200 new jobs in Lee County, North Carolina. Hiring is expected to start this year.

“Our investment in large-scale manufacturing has always been a cornerstone of our strategy to develop and ultimately deliver our important genetic medicines to patients as rapidly as possible,” said Natalie Holles, president and chief executive officer of Audentes. “This new facility in Sanford will support the next phase of our growth as we establish a robust, global supply chain and expand our therapeutic and geographic scope as a part of the Astellas group of companies. We are excited to join the vibrant biopharmaceutical research and manufacturing community that the state of North Carolina has established.”

Audentes is headquartered in San Francisco and focuses on gene therapy. It was acquired by Tokyo-based Astellas Pharma in January.

No specifics were given about what the site will manufacture. In October 2019, Audentes announced positive data from ASPIRO, the clinical trial of AT132 in patients with X-Linked Myotubular Myopathy (XLMTM). AT132 is an AAV8 vector that contains a functional copy of the MTM1 gene. XLMTM is a serious, life-threatening, rare neuromuscular disease marked by extreme muscle weakness, respiratory failure and early death.

The company indicates it hopes to submit a Biologics License Application (BLA) for AT132 to the U.S. Food and Drug Administration (FDA) later this year.

An announcement ceremony was held in the industrial shell building the company is buying in the Central Carolina Enterprise Park. It is about 45 miles southwest of Raleigh.

Gov. Roy Cooper stated, “With our powerhouse research centers and highly skilled workforce, biotech pioneers recognize North Carolina’s role as a leader in the life sciences. Lee County is a perfect fit for Audentes as they seek to become a global leader in genetic medicines.”

The employees at the new factory are expected to earn an average salary of $83,900, which is a little over twice the Lee County average of $41,800. If Audentes hits hiring milestones, it will qualify for a state Job Development Investment Grant worth up to $3.7 million.

The county and the city of Sanford are also offering $5.7 million incentives, which includes almost $400,000 in training support from the North Carolina Community College System.

Audentes chose the location over California, Massachusetts and Colorado.

“In every interaction, I was impressed with Audentes’ patient-centric approach to developing their AAV-based gene therapy to transform the lives of affected patients and families,” said Laura Rowley, NCBiotech’s director of life science economic development. She led the Center’s outreach activity with Audentes. “Their decision to grow in North Carolina reflects the Research Triangle region’s specialized training capabilities and strengths in gene therapy and biomanufacturing. The passion and focus of the Audentes team makes me confident that they will be an outstanding addition to North Carolina’s gene therapy community.”

Audentes is acting as the Center of Excellence for Astellas’ newly founded Genetic Regulation Primary Focus.

“Audentes Therapeutics is joining one of the nation’s top life science clusters,” said Anthony M. Copeland, North Carolina’s Commerce Secretary. “North Carolina has the largest biomanufacturing workforce in the nation and a growing concentration of gene therapy scientists, researchers and workers.”

The site of the new plant is quite close to Pfizer’s new gene therapy campus, which is under construction. That $600 million research and manufacturing facility has a 230-acre campus in Sanford and will employ 340 people.

It doesn’t happen that often, but Merck’s checkpoint inhibitor Keytruda (pembrolizumab) received a rejection from the U.S. Food and Drug Administration (FDA). Six all at once, as a matter of fact.

The company had submitted six supplemental Biologics License Applications (sBLAs) to update the dosing frequency of Keytruda to include every-six-weeks (Q6tW) dosing. It was seeking approval of a 400 mg Q6W dose infused over 30 minutes for indications in melanoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, gastric cancer, hepatocellular carcinoma and Merkel cell carcinoma.

The agency issued a Complete Response Letter (CRL), which Merck indicates it is reviewing and will discuss their next plans with the FDA.

The applications were based on pharmacokinetic modeling and simulation data that the company presented at the 2018 ASCO Annual meeting. They also supported a March 28, 2019 approval for the 400 mg Q6W dosing for Keytruda as a monotherapy by the European Commission.

Just last week, Merck positive results from the pivotal Phase III KEYNOTE-355 trial of Keytruda in combination with chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC) whose tumors expressed PD-L1. The trial met one of its dual primary endpoints, progression-free survival (PFS).

An independent Data Monitoring Committee (DMC) ran an interim analysis on the trial, showing that first-line treatment with Keytruda with nab-paclitaxel, paclitaxel or gemcitabine/carboplatin had a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone. The DMC recommended the trial continue without changes to evaluate the other dual primary endpoint, which is overall survival (OS).

“Triple-negative breast cancer is an aggressive malignancy,” said Roger M. Perlmutter, president, Merck Research Laboratories. “It is very encouraging that Keytruda in combination with chemotherapy has now demonstrated positive results as both a first-line treatment in the metastatic setting with this trial, and as neoadjuvant therapy in the KEYNOTE-522 trial. We look forward to sharing these findings with the medical community at an upcoming congress and discussing them with the FDA and other regulatory authorities.”

TNBC is a particularly aggressive form of breast cancer. It has a high recurrence rate within the first five years after diagnosis. The triple-negative refers to testing negative for all three hormone receptors, estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2). Many cancer therapies target one or more of these hormone receptors, and this lack of all three makes it difficult for therapies to target the cancer. TNBC affects about 15-20% of breast cancer patients.

The company is having a busy year so far. In addition to these two stories, last week four African countries, including the Democratic Republic of the Congo (DRC), approved Ervebo, the company’s Ebola vaccine.

And as part of its 2019 full-year and fourth-quarter reporting, Merck announced it is spinning off products from its Women’s Health, Legacy Brands, and Biosimilars businesses. It plans to launch a new, independent, publicly-traded company to handle those products. No name for the new company has been announced.

“Over the past several years, we have purposefully shifted the focus of our efforts and resources to our best opportunities for growth,” said Kenneth C. Frazier, chairman and chief executive officer of Merck.

Those key pillars are Oncology, Vaccines, Hospital and Animal Health. And it’s clear that the foundation of the Oncology pillar is Keytruda.

The new company will decrease Merck’s Human Health manufacturing footprint by about 25% and the number of Human Health products by about 50%.