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Regeneron is eying potential regulatory approval of its treatment for a rare bone disease after Phase II clinical data showed an almost 90% reduction in the formation of new lesions in patients with fibrodysplasia ossificans progressiva (FOP).

This morning, Regeneron Pharmaceuticals announced the results from the mid-stage LUMINA-I study, which was evaluating garetosmab (REGN2477) in patients with FOP, an ultra-rare genetic disorder with no approved treatments that leads to abnormal bone formation resulting in skeletal deformities, progressive loss of mobility and premature death. Following 28 weeks of treatment, data from the Phase II study showed garetosmab decreased total lesion activity, both new and existing lesions, compared to placebo by 25% as measured by PET bone scans. That result was driven by a nearly 90% decrease compared to placebo in the number of new lesions as measured by the same scans, the company said. Additionally, Regeneron said patient-reported flare-ups were cut in half. Investigator-reported adverse events flare-ups were 10% for garetosmab and 42% for placebo, the company added.

As a result of the study, Regeneron said it plans to discuss regulatory submission with regulatory authorities and is also planning a pediatric trial in this indication.

George D. Yancopoulos, Regeneron’s president and chief scientific officer, said the work with garetosmab is the culmination of decades of research in FOP that began in the 1990s.

“This disease is relentless and devastating, leaving many patients wheelchair-bound or locked in a position unable to move, with a dramatically curtailed lifespan. We believe garetosmab may offer important new hope that can potentially transform the course of FOP and look forward to working closely with the FDA and other regulatory authorities to make garetosmab available,” Yancopoulos said in a statement.

FOP is an ultra-rare disease in which muscles, tendons and ligaments are progressively replaced by bone, a process known as heterotopic ossification (HO). There are approximately 800 patients across the globe known to have FOP and a number of other patients who have gone undiagnosed or misdiagnosed, Regeneron said. Most people with FOP are wheelchair bound by 30 years old and the median age of survival is approximately 56 years. Death often results from complications, such as pneumonia, heart failure and aspiration stemming from HO and loss of mobility in the chest, neck and jaw.

Garetosmab is a monoclonal antibody that reduces the formation of heterotopic bone lesions by neutralizing the Activin A protein. Actavin A is a critical protein for the development of HO. In 2017, the U.S. Food and Drug Administration granted Fast Track designation for garetosmab for the prevention of HO in patients with FOP. It has also been granted Orphan Drug designation.

Regeneron’s head of research and development Aris Economides said the data from the LUMINA-I trial proves the hypothesis that Activin A is required for the formation of new heterotopic bone lesions in people with FOP. Inhibiting Activin A with garetosmab reduces the occurrence of abnormal bone development and flare-ups, which provides a “true opportunity for a disease-modifying therapy for FOP,” Economides said.

Detailed results from this trial will be used as the basis of regulatory submissions, the company said. The data will also be submitted for presentation at a future medical conference.

Regeneron isn’t the only company working on a treatment for FOP. France-based Ipsen is also developing a treatment called palovarotene. However, last month, the FDA placed a partial clinical hold on palovarotene, due to some safety concerns in pediatric patients.

Merck’s checkpoint inhibitor Keytruda (pembrolizumab) continues moving toward the projections of becoming the world’s best-selling drug. The company announced that the U.S. Food and Drug Administration (FDA) had approved the anti-PD-1 therapy as a monotherapy for patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are not eligible for or have elected not to undergo cystectomy.

The approval was built on data from KEYNOTE-057. This trial looked at 96 patients with this indication. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after being initially tumor-free after adequate BCG therapy, or T1 disease after a single course of BCG.

Before treatment, all patients underwent transurethral resection of bladder tumor (TURBT) to remove all resectable disease. However, residual CIS that was able to be completely resected was allowed. Patients with muscle-invasive locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition requiring immunosuppression were not included.

“Today’s approval of Keytruda reinforces our company’s commitment to expanding existing treatment options for certain patients with high-risk, non-muscle invasive bladder cancer,” said Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories.

Ebbinghaus added, “As the first anti-PD-1 therapy approved in this setting, Keytruda will be a new clinical option for a patient population that previously had limited FDA-approved therapies available.”

In the trial, patients received 200 mg of Keytruda every three weeks until they hit unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. The tumors were assessed every 12 weeks for two years and then every 24 weeks for three years. Patients whose disease did not progress could be treated for up to 24 months.

The major efficacy outcome measures were complete response and duration of response. About 11% of patients discontinued Keytruda because of adverse reactions, the most common being pneumonitis. Adverse reactions that caused interruption of treatment occurred in 22% of patients, with the most common being diarrhea and urinary tract infections. More than a quarter, 28%, of the patients had serious adverse reactions, with the most common being pneumonia, cardiac ischemia, colitis, pulmonary embolism, sepsis, and urinary tract infection.

“High-risk, non-muscle invasive bladder cancer is a serious disease, characterized by frequent recurrences and progression,” said Arjun V. Balar, associate professor of Medicine and director of Genitourinary Medical Oncology at NYU Langone Health’s Perlmutter Cancer Center. “Historically, patients with high-risk, non-muscle invasive bladder cancer with CIS whose cancer is unresponsive to BCG treatment had limited non-surgical treatment options. As a physician who specializes in the management of bladder cancer, it is encouraging to now have a new treatment option for these patients.”

Keytruda is in more than 1,000 clinical trials in numerous cancers and treatment settings. It is currently approved for melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma and renal cell carcinoma.

With nearly two million new cases and a million deaths each year in India, the war against cancer is amongst the most pressing crises in the country. Over the years, Eight Roads  has had the privilege of partnering with companies who are working towards building weapons to help fight this war, for example, in India, Laurus Labs, amongst the world’s largest manufacturer of generic oncology active pharmaceutical ingredients and CORE Diagnostics, one of the country’s leading providers of high end oncology diagnostics. Now, with our investment in Immuneel, there is an opportunity to build the first cutting-edge oncology therapeutics platform focussed on the Indian population.

What is CAR-T therapy?

Immuneel has been founded with the aim of delivering cellular immunotherapies like CAR-T (Chimeric Antigen Receptor-T cells) for the management of cancers, at a price point that would enable relatively widespread access across the country.

The treatment of cancer with traditional drugs often proves inadequate, as tumour cells can find refuge in hard to access locations and then mutate to build resistance, leading to cycles of remission and relapse. CAR-T therapies, where patients are infused with live immune cells that have been genetically programmed to specifically target cancer, offer a more responsive option capable of hunting tumour cells down to their last remnants.

Globally, the two marketed products by Novartis and Gilead, have begun to gain traction in select markets like the US despite their exorbitant pricing, as evidence mounts from a growing base of patients who have achieved lasting remissions from otherwise terminal diseases. Sadly, these therapies are unavailable in India, though the country has already established the tertiary healthcare infrastructure required for administering these treatments (~1900 bone marrow transplants were performed in India last year, a procedure that requires nearly comparable clinical infrastructure).

Immuneel and its ambitions

The company is targeting a range of CAR-T programs, including next generation therapies, to capture the full potential of this therapeutic modality. First generation therapies target blood cancers, and efforts are now ongoing to address the broader base of solid tumours.

There is also work being done on optimizing the mix of cell types infused into patients to increase efficacy and create an improved memory function for long term targeting of tumour cells that manage to survive the initial immune onslaught. Another major stream of research on CAR-T therapies is the potential for allogenic treatments. While therapies today involve the collection and re-infusion of a patient’s own immune cells, allogenic therapy would enable cells from a given donor to be used across a range of patients, thereby significantly lowering production cost and operational complexity. 

The founding team

Immuneel has been put together by an exceptional set of founders including Kiran Mazumdar Shaw, one of the leading figures in our biopharmaceutical industry, Dr. Siddhartha Mukherjee, an oncologist with the Columbia University Medical Center and a Pulitzer Prize winning author of “The Emperor of All Maladies: A Biography of Cancer”, and Dr. Kush Parmar, an experienced biotech entrepreneur and Managing Partner at Boston-based 5AM Ventures. With their support, the company has access to some of the leading CAR-T programs worldwide, an ability to establish relationships with relevant stakeholders in the Indian healthcare ecosystem and the reach to create a world-class team. Operations at the company’s state-of-the-art R&D and manufacturing facility in Bangalore are helmed by a handpicked team of scientists, led by Dr. Arun Anand, a seasoned bio-therapeutics professional. 

These are still early days in the evolution of CAR-T and other cellular immunotherapies, with leading signs indicating that they could provide a vital weapon in the fight to contain cancer. We are excited to support Immuneel in its mission to save lives with breakthrough therapies, and build a company with the potential to galvanize the next wave of innovation in the biotech landscape.

Dive Brief:

• Abbott on Monday said FDA approved a less invasive surgical technique for its HeartMate 3 heart pump that will spare more patients from open heart surgery to have the device implanted.
• Called lateral thoracotomy, the alternative procedure enables the mechanical HeartMate 3 pump to be implanted via an incision between the patient’s ribs, resulting in less bleeding and a shorter recovery time, the company said.
• Abbott said two studies supported the FDA approval: a postmarket registry called Elevate and the LAT single-arm multicenter feasibility trial. Both showed patients who underwent the less invasive approach had lower rates of bleeding requiring surgery, infection and arrhythmias compared to patients who had open heart surgery.
  

  Dive Insight:

  Abbott and Medtronic, its key competitor in the market for ventricular assist devices, continue to invest in improvements to the life-extending pumps that provide circulatory support to patients with advanced heart failure. Medtronic gained FDA approval for use of a thoracotomy procedure for its HeartWare LVAD in 2018.

  The devices help pump oxygenated blood from the left ventricle into the ascending aorta and can be used as a bridge to a heart transplant or as destination therapy for patients who are not candidates for a donor heart. HeartMate 3 was approved in 2017 for patients awaiting a transplant and in 2018 as a destination therapy. Abbott said in 2019 that some HeartMate recipients have lived with the device for more than 10 years.

  HeartMate 3 is the third generation of the device that Abbott gained as part of its $25 billion acquisition of St. Jude Medical in 2017. St. Jude bought HeartMate developer Thoratec for $3.4 billion in 2015.

  Medtronic acquired its LVAD system in 2016 when it paid $1.1 billion to buy HeartWare International. The technology continues to evolve, with Medtronic announcing in October that it received FDA’s breakthrough designation to develop a fully implantable LVAD that would eliminate the need for a cable to connect the implant to an outside power source.

  In December, Abbott encountered two issues related to the power supply for HeartMate 3 that prompted the company to warn doctors of the potential for serious injury to patients. Incorrect connection of the device cable when exchanging controllers can result in loss of electrical power to the pump, Abbott said. The problem was linked to a death rate of 0.05% and a rate of hemodynamic compromise, in which blood flow from the device is reduced or stopped, of 0.07%, the company said.

  Abbott also said it had received reports that excessive static electricity had caused power loss to patients’ HeartMate mobile power unit modules. Two serious injuries due to hemodynamic compromise were reported in connection with the problem.

Natural Language Generation (NLG) company and document drafting technology supplier Litera have announced a partnership with Yseop  to provide life science companies with more efficient and effective management of regulatory compliance processes.

Bringing a new drug to market takes between 10 and 15 years and costs between $1.5 and $2 billion. In a context of heightened regulatory scrutiny and obligations, relying on manual reporting systems and complex, resource-intensive and time-consuming processes, can jeopardise the whole investment.

Litera is committed to accelerating the creation, review, formatting, and standardisation of documents to offer the fastest path to compliance, with a dedicated offering for regulatory, medical affairs, and clinical operations specialists. Its solution portfolio (DocXtools for Life Sciences, Change-Pro Premier, and Content Companion) offers a best-of-breed combination to streamline and accelerate high-quality submissions.

Matt Miller, Litera director of product management said: “Patients are waiting. This is the most important driving factor we bear in mind when working with life science companies. We are always looking for technologies that can help them complete submissions faster. Yseop’s expertise in AI-powered intelligent automation blends in well with our document processing technology and we are proud to be able to work collaboratively on offering the best approach to streamline regulatory submission.”

Working closely with some of the global leading pharmaceutical companies, Yseop has provides automated reporting solutions for medical writers, built on advanced artificial intelligence NLG technology. By automating some of the manual reporting sections needed to ensure compliance and safety, Yseop’s NLG solution helps pharmaceutical companies save time and money and get drugs to market faster.

Emmanuel Walckenaer, CEO of Yseop, said: “NLG offers this unique ability to help scale human expertise and regulatory submission is one of the areas where the benefits it delivers proves the more valuable. We share with Litera the urge to provide Life Sciences company with the best technology available. We are delighted to enrich our respective ecosystem and are eager to have our joint clients combine our technologies and achieve new levels of regulatory compliance efficiency.”

PharmaLex Group has completed its merger with CompliMed in the United Kingdom. CompliMed is the UK’s leading Healthcare Compliance Consultancy specialising in the ABPI Code of Practice. Their services include training, e-learning, outsourcing, audits, SOPs, medical review and final signatory support.

“By joining forces with CompliMed, PharmaLex will extend its services in healthcare compliance,” the company said in a statement. “This will provide a strategic fit where PharmaLex already acts as medical reviewer, Information Officer or certifying signatory in line with national requirements in European countries.

“The merger with PharmaLex is a major milestone for CompliMed,” added Dr Rina Newton, managing director, CompliMed. “We are excited to be able to strengthen the services they offer as we become part of a larger organisation with an excellent reputation and significant global footprint.” 

“CompliMed are a perfect fit for PharmaLex.” said Dr Thomas Dobmeyer, CEO PharmaLex. “Our strategy is to build a European service line that offers healthcare compliance in all European countries and the US. CompliMed are trusted by their customers for their high-quality standards. Having such a dependable team join PharmaLex is a real asset as both organisations are committed to outstanding service levels and delivering exceptional client solutions.”

Wearables player Reliefband Technologies, has announced the unveiling of its new travel and sport therapeutic devices.

The company specialises in technology that aims to prevent and treat nausea and vomiting symptoms, and has received have received U.S. Food and Drug Administration (FDA) expanded indication clearance.

Both of the new devices, which are on show at CES 2020, offer user-controlled therapy for the prevention and treatment of nausea and vomiting associated with anxiety, hangovers, and physician-diagnosed migraines, as well as motion sickness, chemotherapy, morning sickness, and as an adjunct to antiemetics for postoperative surgery.

The over-the-counter transdermal neuromodulation devices are applied to the underside of the wrist. Reliefband works by emitting electrical pulses that stimulate the underlying median nerve. The signals generated on the underside of the wrist then flow to the central nervous system where they work, via the vagus nerve, to normalise stomach rhythms that cause nausea and prevent it.

Rich Ransom, president and CEO of Reliefband Technologies, said: “There are more than 38 million people in the U.S. who suffer migraines and the most common associated symptoms are nausea and vomiting. These newly-cleared indications mark an important step in our mission to mitigate the serious health issues and utter misery associated with nausea. We will continue to innovate our Reliefband technology, providing relief to those who suffer debilitating symptoms stemming from migraines, hangovers, anxiety and more.”

The devices can be used either before or after nausea and vomiting symptoms start and can be left on as long as symptoms subsist.

Reliefband Travel is a limited use wearable device designed for casual travellers who deal with nausea symptoms on a sporadic basis. There are three single-use models which work at a moderate level of intensity for 48 hours, 72 hours, or seven days and can be turned on and off as needs arise. These devices function with an included set of non-replaceable batteries and will be popular options for unsteady flyers, cruise vacationers or others who suffer from motion sickness or travel-related anxiety. 

Reliefband Sport is a waterproof device, which includes a built-in rechargeable battery that, when fully charged, will last an extended period of time on the medium intensity level. Six intensity levels can be toggled allowing users to find the precise setting that’s optimal for their needs at any moment.

The device will be launched with immediate effect. Approval of the CE mark is based on data from Polyganics’ Encase I clinical trial, evaluating the safety and performance of Liqoseal in reducing cerebrospinal fluid (CSF) leakage after elective cranial surgery. Three-month follow-up results showed the absence of CSF leakage, as confirmed by MRI, no clinically significant swelling, and no device-related adverse events following surgery.

Initially, Polyganics will commercialise Lioqseal in selected European countries. During 2020, the Company will then grow its network with the addition of multiple distributors throughout Europe.

Polyganics is also preparing to launch Liqoseal in selected non-European countries. In addition, arrangements are underway for the start of Encase II, a randomised controlled trial, which will enable the Company to submit the patch for pre-market approval to the US Food and Drug Administration (FDA).

Rudy Mareel, CEO of Polyganics, said: “CSF leakage remains a devastating complication of neurosurgical procedures and represents a significant patient burden with high associated cost. The CE approval of this product is testament to the strength and quality of the clinical data from Encase I, showing that Liqoseal establishes effective and enduring watertight dural closure. This is a key milestone in our journey to deliver our dural sealant patch to surgeons and patients in Europe and ultimately worldwide.”

Undeterred by two clinical failures for its cancer immunotherapies in 2019, Transgene has kicked off the New Year by starting trials of a new vaccine for ovarian and head and neck cancers.

The French biotech is partnering with artificial intelligence (AI) specialist NEC on the new programme – called TG4050 – which according to the partners “moves therapeutic vaccination into the digital age.”

TG4050 has been designed using an NEC technology that uses AI to discover cancer cell mutations – or neoantigens – that can be used as targets for medicines. Cancer cells accumulate mutations and each patient has a specific set that are unique to their tumour.

The Neoantigen Prediction System is drawn from a dataset of immune data generated around 20 years and can select the neoantigens most likely to stimulate an immune response against a cancer cell line, according to NEC, a Japanese IT giant.

TG4050 targets up to 30 of those patient-specific neoantigens, which are incorporated into the genome of the modified vaccinia virus Ankara (MVA) viral vector. It is the lead candidate in Transgene’s myvac personalised cancer vaccine technology platform.

The first patients have now been enrolled into the two phase 1 studies at the Mayo Clinic in the US and Toulouse Oncopole in France, which will test TG4050 in patients with head and neck cancer who have a high risk of relapse after surgery and patients with ovarian cancer after surgery and adjuvant therapy.

It was also given a green light for a trial in head and neck cancer by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) last year.

The new trials come a month after Transgene was forced to abandon a first-line non-small cell lung cancer (NSCLC) therapeutic vaccine candidate – TG4010 – after disappointing results in a phase 2 trial as a combination with Bristol-Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab).

That in turn followed the demise of Sillajen-partnered oncolytic virus therapy Pexa-Vecin August, placing more importance on TG4050 and Transgene’s myvac programme, as well as oncolytic virus candidates partnered with AstraZeneca last year and other pipeline projects like TG4001 for head and neck squamous cell carcinoma (HNSCC).

Transgene’s share price has been on a downward trajectory over the last few months, trading well below its 52-week high of €3.30, but was up 4% in morning trading today at around €1.65.

In a statement, the French biotech said it has also set up the manufacturing capacity that it needs to prepare the individualised batches of TG4050 for the clinical development programme.

“As each patient’s cancer is unique, we have developed a therapy that turns their solid tumour’s genetic signature into a powerful highly specific anticancer weapon,” said Transgene’s chief executive Philippe Archinard.

“We are convinced that TG4050, which is at the crossroad of immunotherapy and big data sciences, will herald the start of a new era in the fight against cancer,” he added.

US-based Merck & Co has forged an R&D tie-up with Taiho and Astex Pharmaceuticals, focused on developing small molecule drugs targeting the KRAS gene that has become the subject of intense focus in pharma after a landmark trial from Amgen last year.

Big pharma has turned its attention to KRAS after Amgen published results of an early trial of its AMG 510, which showed an effect on cancers with this common cancer mutation for the first time.

Amgen’s data announced at the American Society of Clinical Oncology (ASCO) last year showed that five out of 10 patients with cancers expressing the KRAS G12C mutation partially responded to the therapy – a first in pharma and enough to drive up the company’s share price substantially.

Since then Amgen has unveiled data showing AMG 510 kept cancer at bay in 10 patients with non-small cell lung cancer and shrank tumours in more than half of them.

Several other big pharma companies have joined the fray, with Novartis signing an R&D deal with KRAS biotech Mirati in July.

Eli Lilly is also developing a KRAS G12C targeting drug, LY3499446, and Boehringer Ingelheim is working with Indian pharma Lupin to develop a KRAS drug too.

Merck & Co’s agreement with Taiho and Astex, a subsidiary of Japan’s Otsuka, is worth up to $2.5 billion if all pre-determined clinical and regulatory goals are met although the upfront payment from the big US pharma is relatively small at just $50 million.

There will be tiered royalties from sales and Merck will fund research and development and will be responsible for marketing of products globally.

The R&D tie-up will be based around Taiho’s small drug discovery technology, and Taiho has retained co-marketing rights in Japan and an option to promote in specific areas of South East Asia.

KRAS mutations are estimated to occur in more than 90% of pancreatic cancers and approximately 20% of non-small cell lung cancers and is associated with poorer outcomes.