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Dive Brief:

• A Medtronic insulin pump hardware malfunction that prompted the company to alert certain MiniMed customers late last year has been linked to 26,421 complaints, 2,175 injuries and one death, FDA said in a noticeissued Wednesday.
• Medtronic warned customers Nov. 21 that a potential missing or broken retainer ring, which ordinarily helps secure the insulin cartridge’s position in the pump’s reservoir compartment, could lead to under or over delivery of insulin, thereby increasing risk for hypoglycemia and hyperglycemia and ultimately loss of consciousness, seizure or death.
• Now the agency has categorized the action affecting more than 320,000 U.S. devices as a Class I recall, reflecting the concern that use of affected devices may result in serious injury or death.
  

  Dive Insight:

  In total, 322,005 devices in the U.S. are covered by the recall, FDA detailed Wednesday. Affected devices include all 630G pumps distributed between September 2016 and October 2019, and 670G pumps distributed between June 2017 and August 2019.

  The latter model was Medtronic’s big diabetes innovation approved by FDA in 2016 as the first automated insulin delivery device. In the years since, companies like Tandem and Insulet have broken through with their own diabetes management products, but Medtronic hopes to retake share with its forthcoming 780G pump.

  That device, which Medtronic is calling a personalized hybrid closed loop system, is designed to automatically deliver correction bolus doses in anticipation of, or when a user experiences, prolonged high glucose levels. Medtronic expects to present pivotal trial data on the device at the American Diabetes Association meeting in June.

  There are no new instructions to customers, a Medtronic spokesperson confirmed Wednesday. The company maintained earlier guidance that customers should contact Medtronic for a replacement pump if, upon examination, the reservoir doesn’t lock into the pump or if the retainer ring is loose, damaged or missing. Medtronic also advised that users check for proper function of the retainer ring if the pump is dropped by accident and at every set change.

  In the past week, FDA also sent a Class I recall notice regarding nearly 3,600 GE Healthcare anesthesia systems that may have problems with mechanical ventilation.

  Medtronic is scheduled to report recent financial results and discuss plans for the coming months during an earnings call Tuesday.

In the highly competitive market for inflammatory diseases such as Crohn’s, pharma companies are looking for ways to maximise benefits of already approved drugs, as well as developing new ones.

Johnson & Johnson’s Janssen unit is taking this approach with its well-established Stelara (ustekinumab), which is fighting it out against the likes of UCB’s Cimzia (certolizumab pegol) and Takeda’s Entyvio (vedolizumab).

While it waits for trial results to see if its newer anti-inflammatory drug Tremfya works in Crohn’s, Janssen is also trying to see if using ultrasound monitoring can improve outcomes with Stelara.

The formulation tested in the phase 3b STARDUST trial is also new, with patients receiving an intravenous (IV) induction dose of around 6mg/kg followed by a 90mg subcutaneous (SC) injection at week eight.

The trial involved a “treat-to-target” strategy, where outcomes such as endoscopic response, biomarkers and clinical symptoms guide use of the medication.

“Treat-to-target” is different from the standard treatment approach, where dosing is decided by characteristics such as a patient’s weight.

At week 16, patients who achieved an at least 70 point decrease in Crohn’s Disease Activity Index score, were randomly selected to receive the “treat to target” strategy or standard care.

For now it’s not fully clear whether the approach has worked as 48 week data is coming out further down the line.

But at week 16, 79% of patients with moderately to severely active Crohn’s disease (CD) achieved clinical response and 67% were in clinical remission after receiving the IV dose followed by the SC of Stelara (ustekinumab), open label.

Intestinal ultrasound (IUS) responses were assessed and were detected as early as week four.

Professor Silvio Danese, head of the Inflammatory Bowel Diseases Center at Humanitas Research Hospital, Milan, Italy and principal investigator, said: “Crohn’s disease patients may respond to treatment while continuing to experience internal inflammation that can cause irreversible damage.

“These patients may benefit from a more proactive, robust treatment approach and less invasive monitoring methods.

“I am encouraged by these data, that demonstrate the potential clinical utility of the noninvasive IUS method in helping guide treatment of CD and look forward to forthcoming data that may help us better understand the possible benefits of a treat-to-target strategy.”

Week 16 data and IUS response data from STARDUST are being presented as digital oral presentations at the 15th Congress of the European Crohn’s and Colitis Organisation (ECCO) this week.

Johnson & Johnson has announced it has expanded a collaboration with a US government agency to hasten development of its coronavirus vaccine, as fears mount about the scale of the outbreak that is now called COVID-19.

As previously reported by pharmaphorum, J&J is one of the big pharma companies that is actively looking for vaccines for the novel coronavirus strain, which causes the disease now called COVID-19 by the World Health Organization.

The company said it will intensify work with the Biomedical Advanced Research and Development Authority (BARDA), part of the US Department of Health & Human Services.

The collaborative partnership with BARDA builds on J&J’s response to the disease – the company is already working with several other partners to develop a vaccine and screen its library of antiviral molecules for treatments that could provide relief for people in China and elsewhere.

In the latest agreement J&J’s Janssen pharma unit and BARDA will contribute to R&D costs and rapidly advance the initial stages of the COVID-19 vaccine development programme.

BARDA will fund accelerated development of a vaccine into phase 1 studies, with options for additional funding to progress a promising candidate.

In parallel, Janssen will scale up production and manufacturing capacity, using the same technologies that were used with its investigational Ebola vaccine, which is currently deployed in the Democratic Republic of the Congo and Rwanda.

The AdVac and PER.C6 technologies were also used to construct the company’s Zika, RSV and HIV vaccine candidates.

J&J did not give a timeline for development, but chief scientific officer Paul Stoffels has said on record that a vaccine could take a year to develop even with the latest technology.

In a separate development Chinese drugmaker BrightGene Bio-Medical Technology said that it has started mass producing an experimental drug from Gilead that has potential to fight COVID-19.

The Suzhou-based firm said it has the technology to make the active pharmaceutical ingredients of remdesivir.

Remdesivir is not licensed or approved but has shown signs of working in infected patients and is being tested on hundreds of patients in clinical trials in Wuhan.

BrightGene said in a statement filed with the Shanghai Stock Exchange that it will look to license the patent from Gilead, conduct clinical trials and get regulatory approval so that it can sell the drug on the market.

Gilead last week said it invented remdesivir and has patented it in China, including filing patent applications for use on coronaviruses.

Last week the state-run Wuhan Institute of Virology applied for a patent on use of remdesivir, in a move that it said was to protect national interest.

Shares of LogicBio have plunged more than 25% in premarket trading after the company disclosed late Monday that the U.S. Food and Drug Administration (FDA) placed a clinical holdon its proposed gene therapy treatment for methylmalonic academia (MMA).

In January, Cambridge, Mass.-based submitted an Investigational New Drug Application to initiate a Phase I/II trial of LB-001, a recombinant adeno-associated viral vector with human methylmalonyl-COA mutase (MMUT) gene for the treatment of MMA. But, before that trial could ever receive the green light, the FDA has demanded answers to a few undisclosed clinical and nonclinical questions. While the concerns raised by the FDA have not been made public, in the past, there have been some questions over potential downstream side effects from gene-editing treatments, such as CRISPR. The company believes that its technology eliminates those concerns.

LogicBio said it anticipates answering the questions raised by the FDA within 30 days, as required. The company said it will closely work with the regulatory agency in order to resolve the issue as quickly as possible.

LogicBio’s LB-001 is an investigational pediatric genome editing therapy based on the company’s GeneRide technology. LogicBio’s GeneRide technology enables site-specific integration and lifelong expression of therapeutic transgenes, without the use of exogenous promoters or nucleases, the company said. LB-001 is designed to incorporate a functioning version of the faulty human methylmalonyl-COA mutase gene into the genome of MMA patients. In preclinical MMA models, LogicBio has shown that cells into which GeneRide has inserted a transgene demonstrate a selective survival advantage over cells not expressing the transgene. LB-001 has received both orphan drug and rare pediatric disease designations from the FDA.

When LogicBio submitted the IND last month, the company said it would then announce the trial size and endpoints of the Phase I/II trial. The first trial is expected to be in pediatric MMA patients. The company had hoped to launch the trial in the first part of 2020 and have preliminary data available in the second half of the year.

MMA is a rare and life-threatening disease caused by mutations in the MMUT gene. The disease is typically discovered in the first month of an infant’s life and prevents the body from properly processing certain fats and proteins. By failing to process those fats and proteins, it creates a buildup within the body that can lead to significant morbidity and mortality, including infections, neurodevelopmental disabilities and chronic kidney disease. It is estimated that there are approximately 1,000 to 1,500 MMA patients in the United States and about 5,100 patients across the globe.

There are currently no approved treatments for methylmalonic academia in the United States.

Shares of LogicBio are trading at $7.75 in the premarket. The stock closed at $10.45 per share Monday.

Alzheimer’s disease continues to be a tough nut to crack. A specially designed clinical trial that was the first disease prevention trial to study Alzheimer’s disease drugs with different mechanisms of action from two different pharmaceutical companies failed to hit the primary endpoint.

DIAN-TU-001 is a Phase II/III trial that tested two therapies compared to placebo, Genentech and Roche’s gantenerumab and Eli Lilly and Company’s solanezumab.

The overall trial was founded in 2010 and funded by Eli Lilly and Company, Roche and Genentech, the National Institutes of Health, and other donors.

First, Genentech, a Roche company, announced that the gantenerumab arm of the Phase II/III DIAN-TU-001 trial did not meet the primary endpoint in an early-onset, inherited form of Alzheimer’s. This form of Alzheimer’s is known as autosomal dominant AD (ADAD) and makes up less than 1% of cases.

The trial was sponsored by Washington University School of Medicine in St. Louis. Gantenerumab is an antibody that binds to aggregated forms of beta-amyloid and removes beta-amyloid plaques.

The primary outcome measure for the study was the DIAN Multivariate Cognitive Endpoint, which is designed to assess cognitive performance in ADAD patients. The trial evaluated 194 patients for up to seven years, with the average around five years. All the patients in the trial carried a genetic mutation that causes inherited AD. It included patients who didn’t yet have symptoms at the time of enrollment as well as people who had mild symptoms.

“We are very grateful to all those involved in this study and hope the data can further contribute to the science and collective understanding of this complex disease,” said Levi Garraway, chief medical officer and head of Global Product Development for Genentech. “Although DIAN-TU didn’t reach its primary endpoint, the trial represents the first of its kind and a bold undertaking by all partners involved. Given its experimental nature, we are unable to draw firm conclusions about the impact of gantenerumab in autosomal dominant Alzheimer’s disease. This outcome does not reduce our confidence in the ongoing Phase III GRADUATE clinical program.”

Eli Lilly and Company’s solanezumab also failed to meet the primary endpoint. Solanezumab is also an antibody against amyloid.

The primary efficacy analysis of the solanezumab arm was of 50 patients on solanezumab and 40 receiving placebo. The minimum four-year treatment period was finished by 36 patients on solanezumab and 32 on placebo. The early dose was 400mg every four weeks but was later amended to increase the dose to about 25% of the total doses at the 1600mg level.

“Our first attempt to slow Alzheimer’s before symptoms manifest is the result of the heroic commitment of patients and families at risk for dominantly inherited Alzheimer’s, leading global academic researchers, the NIH, the Alzheimer’s Association, philanthropic supporters, the DIAN-TU Pharma Consortium, government and regulatory colleagues, and pharmaceutical companies whose drugs are being tested,” said Randall J. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology, director of DIAN-TU, and study’s principal investigator. “It wouldn’t have been possible without all stakeholders coming together for the cause to stop Alzheimer’s disease.”

Although solanezumab failed an Alzheimer’s trial in 2016, it is still being evaluated in the A4 Study in older people who have evidence of amyloid in their brains, but do not show symptoms of memory problems.

Late-stage data released from Regeneron highlights the importance of proactively providing Eylea to patients who have been diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) in order to prevent issues that could lead to the loss of vision.

Based on data from its Phase III PANORAMA study, Tarrytown, N.Y.-based Regeneron said providing these types of patients with proactive treatments of Eylea (aflibercept) Injection 2 mg reduced “vision-threatening complications” by 75%, compared to patients who were not treated. The vision-threatening complications include the loss of vision, as well as proliferative diabetic retinopathy, anterior segment neovascularization and center-involved diabetic macular edema. In contrast, the study data showed that more than half of the untreated patients in the Phase III trial (58%) developed vision-threatening complications within two years of starting the trial.

Diabetic retinopathy affects about 8 million people and is characterized by microvascular damage to the blood vessels in the retina often caused by poor blood sugar control in people with diabetes.

The results from the study, which were presented this weekend at the Angiogenesis, Exudation, and Degeneration 2020 meeting in Miami, showed a greater benefit for patients treated with Eylea at regular intervals, compared to those who only sporadically received treatment with Eylea. Specifically, the data showed that those patients who received treatment with Eylea every two months benefited the most, Regeneron said. Adverse events remained consistent with the known profile of Eylea, the company said.

Charles C. Wykoff, a retina surgeon and investigator in the PANORAMA trial, said the data reinforces that “regular Eylea treatment” can be effective in reducing the risk of new vision-threatening events among patients with moderately severe to severe non-proliferative diabetic retinopathy.  The trial data shows that more than half of the untreated patients developed those vision-threatening conditions, which “underscores the value of treating patients proactively and regularly,” Wykoff said in a statement.

In addition to the PANORAMA results, Regeneron also presented the rationale for use of high dose Eylea in wet age-related macular degeneration. The company is planning to launch a Phase III high-dose trial in wet AMD in partnership with Bayer this year, and another trial in diabetic macular edema.

“Through millions of injections and eight pivotal Phase 3 trials, EYLEA has built a substantial body of evidence and safety profile. High-dose aflibercept will hopefully build on this standard-of-care therapy and represents our ongoing commitment to ophthalmologic research and development,” George D. Yancopoulos, president and chief scientific officer at Regeneron said in a statement. “We are eager to explore the potential of high-dose aflibercept to deliver sustained vision gains and extended duration of action in patients with wet AMD and DME.”

More than five million women suffer from symptoms of uterine fibroids, with more than half of them estimated to have received inadequate treatment. However, new data released by Myovant shows that concerns of inadequate treatment could soon change.

This morning, Switzerland-based Myovant announced an 88% one-year response rate in the positive Phase III LIBERTY extension study of once-daily, oral relugolix combination therapy in women with heavy menstrual bleeding associated with uterine fibroids. Additionally, the company said women who received the treatment experienced, on average, an 89.9% reduction in menstrual blood loss from baseline at one year. Additionally, Myovant said bone mineral density was maintained through one year in the women who received the treatment. Those results remained consistent with previous studies, the company said.

Uterine fibroids are noncancerous tumors but they can cause debilitating symptoms, including abnormal uterine bleeding, heavy or painful periods, anemia, abdominal pain, backache, increased abdominal girth and bloating, urinary frequency or retention, constipation or painful defecation, pregnancy loss, painful intercourse and, in some cases, infertility. Ayman Al-Hendy, director of Translational Research, University of Illinois College of Medicine, said there are approximately 250,000 women who undergo hysterectomies each year due to uterine fibroids. Having a non-invasive treatment that provides long-term options for these women would be a “game-changer for physicians and millions of women who suffer from this common condition,” Al-Hendy said in a statement.

In the primary endpoint analysis, Myovant reported that 87.7% of women achieved the responder criteria defined as a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction from baseline in menstrual blood loss volume during the last 35 days of treatment. The safety data for relugolix remained consistent with previous studies, the company said. Complete results from the LIBERTY open-label extension study will be submitted for presentation at a future scientific meeting and publication in a medical journal.

Based on the results, Myovant expects to submit a New Drug Application to the U.S. Food and Drug Administration in April 2020. The company also plans to submit the data for regulatory approval in Europe as well.

Relugolix is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces ovarian estradiol production. Ovarian estradiol is a hormone known to stimulate the growth of uterine fibroids and endometriosis. Myovant is developing a relugolix combination tablet for women with heavy menstrual bleeding with associated uterine fibroids and for women with pain associated with endometriosis.

Lynn Seely, chief executive officer of Myovant, said the company is pleased the one-year safety and efficacy data for the relugolix combination therapy remain consistent with the company’s data demonstrating a “predictable and clinically-meaningful reduction in menstrual blood loss while maintaining bone health.”

“We look forward to submitting applications to the regulatory agencies in Europe and the U.S. in the coming months to seek approval for our one pill, a once-a-day potential new treatment for women with uterine fibroids,” Seely said in a statement.

The FDA is due to decide by 10 August whether it will approve a second CAR-T therapy from Gilead’s Kite unit intended to treat mantle cell lymphoma (MCL).

The US regulator has just started a six-month priority review of KTE-X19 for adults with relapsed or refractory MCL, a rare form of non-Hodgkin lymphoma (NHL) that usually affects men over the age of 60 and is considered incurable.

The new CAR-T targets the same CD19 target as Kite’s already-marketed therapy Yescarta (axicabtagene ciloleucel), which is used as a third-line treatment for diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).

It is based on a new manufacturing process that boosts the activity of the CAR-T in diseases like B-cell lymphomas where there is a large burden of circulating tumour cells.

Gilead has also filed for approval of KTE-X19 in Europe, with a verdict from the EMA due before the end of the year.

Both US and EU applications are based on data from the ZUMA-2 trial which was reported at the American Society of Haematology (ASH) meeting last year.

The study showed that the CAR-T achieved a 93% overall response rate in 60 MCL patients who had failed standard therapies, including standard first-line agent Revlimid (lenalidomide) from Bristol-Myers Squibb/Celgene as well as BTK inhibitors such as Johnson & Johnson/AbbVie’s Imbruvica (ibrutinib), AstraZeneca’s Calquence (acalabrutinib) and BeiGene’s recently-approved Brukinsa (zanubrutinib).

ASH presenter Michael Wang of MD Anderson said during ASH that the data showed “the highest response rates to date in patients with prior BTK inhibitor failure.”

Approval would give Gilead its second CAR-T product, and help Gilead justify its $11.9 billion acquisition of Kite in 2017. So far Yescarta hasn’t really lived up to its blockbuster expectations.

Sales of the CAR-T were $264 million in 2018, rising to $456 million last year as it faces off rival therapies like Roche’s antibody-drug conjugate, Polivy (polatuzumab vedotin) in B-cell lymphoma.

KTE-X19 also looks set to be the third to reach the market after Yescarta and Novartis’ CD19-targeting Kymriah (tisagenlecleucel) for B‑cell precursor acute lymphoblastic leukaemia (ALL).

Its closest rival for the final podium place in the US is Bristol-Myers Squibb/Celgene’s lisocabtagene maraleucel (liso-cel) which is heading for an FDA decision on its use in DLBCL before the end of the year.

The FDA has agreed to fast-track its regulatory review of Novartis’ capmatinib in a hard-to-treat form of lung cancer.

Novartis said it has applied for capmatinib, developed in partnership with Incyte, to be marketed as a MET inhibitor for first line and previously treated patients with locally advanced or metastatic MET exon 14 skipping (METex14) mutated non-small cell lung cancer.

The decision to grant a Priority Review, which lasts six months instead of the standard ten months, follows the FDA’s decision to grant Breakthrough Therapy Status in September.

This tag is reserved for drugs that could represent a substantial improvement on standard care for serious diseases.

There are no approved treatments for this form of the disease, which accounts for around 3%-4% of newly diagnosed cases.

The FDA will review data from the 334-patient GEOMETRY mono-1 phase 2 study, which showed an overall response rate of nearly 68% in treatment naïve and previously-treated patients.

Median duration of response was 11.14 months in treatment-naïve patients and 9.72 months in previously treated patients.

The most common treatment-related adverse events across all cohorts were peripheral oedema (42%), nausea (33%), creatinine increase (20%), vomiting (19%), fatigue (14%), decreased appetite (13%) and diarrhea (11%). The majority of the AEs were grades one or two.

Novartis licensed in capmatinib from US biotech Incyte in 2009, gaining exclusive development and marketing rights to the MET inhibitor and certain back-up compounds in all indications.

If capmatinib reaches market, Incyte may become eligible for over $500 million in milestone payments and royalties of between 12% and 14% of global sales by Novartis.

The Swiss pharma has also been sponsoring studies of capmatinib under the licensing agreement.

Capmatinib is part of a new generation of drugs from Novartis, which CEO Vas Narasimhan has earmarked as potential new blockbusters.

The development also means that Novartis is pulling ahead of Germany’s Merck KGaA, which is developing a rival MET inhibitor, tepotinib.

At last year’s American Society of Clinical Oncology (ASCO) conference, Merck said that data from tepotinib could be used as part of a regulatory filing, although it hasn’t announced any further news on this yet.

The Life Sciences sector is expected to demand an extra 133,000 skilled scientific jobs through to 2030 – according to the Life Sciences 2030 Skills Strategy.

The report, published by Science Industry Partnership (SIP) in collaboration with the Association of the British Pharmaceutical Industry (ABPI) and the BioIndustry Association (BIA), with support from the Office for Life Sciences (OLS), indicates the jobs will be in highly specialised roles across the sector.

The research forecasts 133,000 jobs across the entire Life Sciences sector to replace retirees and achieve growth ambitions, of which: 

• 43,000 jobs in Biopharma  
• 90,000 jobs in Medtech
• 55,000 workers to replace retirees across the Life Sciences Sector

Each of the functional areas of the workforce are anticipated to require up to:

• 19,300 jobs in Biopharma R&D 
• 6,400 jobs in Biopharma manufacturing
• 8,000 jobs in medtech R&D
• 46,500 jobs in medtech manufacturing 
• 52,400 Service & Supply jobs across the Life Sciences 

The Life Sciences 2030 Skills Strategy highlights that a number of sector-wide skills issues need to be addressed to fulfil the sector’s full potential, including: 

• Computational skills
• Statistical literacy
• Leadership
• Effective communication
• Inter-disciplinary working
• Translation and commercialisation skills
• Holistic sales and marketing skills

Key recommendations include:

• Producing, implementing and monitoring a Life Sciences Skills Action Plan to oversee and coordinate the delivery of the recommendations, through a partnership approach with key sector stakeholders.
• Developing and funding a sector-based skills policy that joins up the skills and business agendas and meets the ambitions of the Life Sciences Industrial Strategy.
• Continuing to promote, encourage and incentivise the take-up of apprenticeships in all parts of the sector to establish parity of esteem with academic routes.
• Maintaining the UK’s position in the Life Sciences sector, by supporting the facilitation of the transfer and exchange of a global workforce.
• The recommendations are being taken forward in a Skills Action Plan which is currently being finalised in collaboration with key partners and will set out activity, milestones and targets.

Success Factors:

The measure of success will be the extent to which this Strategy and the subsequent Action Plan deliver on the skills priorities highlighted in the UK Life Sciences Industrial Strategy and the Sector Deal 1 and Sector Deal 2, particularly: 

• Attracting and retaining globally mobile talent;
• Increasing the take-up of science, technology, engineering and maths (STEM) subjects;
• Understanding, anticipating, and responding to skills gaps across key occupations;
• Supporting mobility between sectors;
• Supporting training for migration of academic scientists into industry;
• Developing apprenticeships and facilitating take-up of apprenticeships, particularly by SMEs;
• Accelerating convergence at the interface between Life Sciences, computer science, mathematics, statistics, engineering and chemistry in the fields of diagnostics, personalised medicine and data science.

Business and industry minister Nadhim Zahawim, said: “We want the UK to be a science superpower. The creation of new cutting-edge jobs in life sciences will help the UK make rapid progress in areas like early medical diagnosis and manufacturing, as well as helping level up every part of the UK with new opportunities.”

Alex Felthouse, managing director, Eisai Manufacturing and chair, SIP Futures Group, added: “This piece of work represents an important and strategic collaboration between the Life Sciences industry and key trade associations, supported by the Science Industry Partnership. It sets out the recommendations to take skills forward out to 2030 in support of our Life Sciences Industrial Strategy.

“To meet the demand that we have for the future we need to ensure that our industry is attractive to those who are considering joining the sector. We need to make them aware of all of the fantastic opportunities there are across a diverse and exciting range of activities – from research and development through to medicines manufacturing. We also need to ensure we have parity of esteem between different educational routes whether it be traditional academic routes, apprenticeships, vocational studies or ongoing Continued Professional Development.”