Category Archives: Hepatology

Sanofi and Alnylam enter into RNAi therapeutics rare disease alliance

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Sanofi and Alnylam Pharmaceuticals, announced a strategic restructuring of their RNAi therapeutics alliance to optimise development and commercialisation of certain products for the treatment of rare genetic diseases.

Sanofi will obtain global development and commercialisation rights to fitusiran, an investigational RNAi therapeutic, currently in development for the treatment of people with hemophilia A and B.

Global commercialisation of fitusiran, upon approval, will be done by Sanofi Genzyme, the specialty care global business unit of Sanofi. Alnylam will receive royalties based on net sales of fitusiran products.

Alnylam will obtain global development and commercialisation rights to its investigational RNAi therapeutics programmes for the treatment of ATTR amyloidosis, including patisiran and ALN-TTRsc02. Sanofi will receive royalties based on net sales of these ATTR amyloidosis products.

With respect to other products falling under the RNAi therapeutics alliance, the material terms of the 2014 Alnylam-Sanofi Genzyme alliance remain unchanged.

“The restructured alliance reflects Sanofi Genzyme’s sustained interest in the strong potential of Alnylam’s portfolio of genetic medicines. The new structure simplifies operations, providing both parties the agility needed to make these medicines available to patients as quickly as possible once approved,” said Bill Sibold, Executive VP and Head of Sanofi Genzyme.

“This restructuring will enable both parties to maximise the value of each asset and allows us to maintain shared economics across the alliance programme.”

Fitusiran complements Sanofi Genzyme’s rare haematology portfolio and creates a focus on bringing an innovative product to market globally, upon approval, for people living with haemophilia, one of the most common rare diseases.

“This strategic restructuring enables streamlined development and an optimised approach to bringing innovative medicines to patients with ATTR amyloidosis and haemophilia around the world, maximising the commercial opportunities for these programmes,” said Dr John Maraganore, CEO of Alnylam.

“For Alnylam, this provides strategic clarity and operational alignment with regard to the development and commercialisation of patisiran and ALN-TTRsc02. This will allow us to develop both products in a comprehensive manner, potentially addressing the full spectrum of transthyretin mediated amyloidosis disease treatment and prevention. At the same time, we will continue to support and benefit — via royalties — from the fitusiran opportunity through Sanofi’s significant development and commercial leadership.”

This restructuring provides Alnylam with the opportunity to consolidate its ATTR amyloidosis business to maximise its value, and the opportunity for near-term acceleration of product revenue growth based on newly obtained rights to commercialise patisiran around the world, once approved.

In addition, it enables Alnylam to build a global presence and commercial infrastructure that can be leveraged for ALN-TTRsc02 and additional programmes, including givosiran, an investigational RNAi therapeutic for the treatment of acute hepatic porphyrias and cemdisiran, an investigational RNAi therapeutic for the treatment of complement-mediated diseases — where Alnylam has retained global ownership.


Boehringer Ingelheim, TARGET PharmaSolutions Partner to Progress NASH Research

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TARGET PharmaSolutions announced that Boehringer Ingelheim International GmbH has entered into a multi-year strategic partnership for TARGET-NASH.

TARGET-NASH is a longitudinal observational study that evaluates patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). To date, TARGET-NASH has enrolled 2,423 patients at 55 sites. TARGET-NASH will enroll up to 15,000 patients over the coming years. TARGET-NASH is led by an academic steering committee chaired by Drs. Arun Sanyal, MD (Virginia Commonwealth University); Ken Cusi, MD (University of Florida), and Brent Tetri (St. Louis University).

“We are very excited to have Boehringer Ingelheim join TARGET-NASH as an industry partner. We have exceeded our enrollment targets to date, and we are providing valuable real-world data and insight on NASH patients that will have a significant impact on the scientific understanding of the natural history and treatment modalities for NASH,” Meg Powell, CEO of TARGET PharmaSolutions, said. “This data, combined with the TARGET-NASH biorepository and patient reported outcomes, will enable our collaborators to continue to increase their understanding of this growing disease.”

Boehringer Ingelheim has a broad patient centric research and development program in metabolic diseases, encompassing diabetes as well as its contributing factors and complications. NASH is one of the company’s key focus diseases in this therapy area with a high unmet medical need and no treatments currently available. Recently Boehringer Ingelheim has e.g. initiated a Phase II clinical trial program with its investigational NASH treatment BI 1467335. The limited information available regarding NASH epidemiology is complicating the development of new medications. TARGET-NASH has thus been initiated to provide an improved baseline against which to measure the impact of new therapies on medical co-morbidities, natural history, and hepatic, cardiovascular, and endocrine-associated outcomes ultimately enabling the development of better treatments for NASH patients.

The TARGET model organizes a community of stakeholders, including pharmaceutical manufacturers, key opinion leaders, regulatory agencies, investigators, and patient advocacy groups, around a specific disease to generate real world evidence about the natural history of the given disease, current treatment paradigm, and patient outcomes.


MSD cuts 1,800 jobs in US operations restructure

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MSD has revealed its intention to cut 1,800 sales positions from its workforce in the US.

Across the total number, the cuts include the elimination of US sales teams in primary care, endocrinology and hospital chronic care. In their place, the company will add 960 positions with the formation of a new chronic care sales force.

This new force will focus on key products in the company’s pipeline including its diabetes treatment Januvia (sitagliptin) and insomnia therapy Belsomra (suvorexant) in addition to women’s health and respiratory disease products.

It should be noted however that this still leaves 840 positions which will not be replaced, and the company has confirmed it will not be shifting the roles to outside the US.

The move follows MSD’s decision not to seek regulatory approval for its cholesterol therapy anacetrapib after it failed to achieve adequate results during clinical trials, as well as the discontinuation of its development of a drug combination to treat chronic hepatitis C last month.

“This is part of ongoing prioritisation efforts and the ebb and flow of our business means that at the same time we’re eliminating certain US jobs, we’re also adding new US jobs in growth areas,” the spokeswoman explained, continuing “these changes are part of ongoing company-wide efforts to sharpen Merck’s focus on innovative R&D that addresses significant unmet medical needs and on our best opportunities for growth, while reducing overall costs.”


First patient treated with microscopic beads pre-loaded with a targeted cancer drug and visible on CT scans

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Researchers from the UCLCancer Institute and BTG plc have begun the first clinical trial of an experimental treatment for liver cancer using X-ray imageable microscopic beads loaded with a targeted anti-cancer drug placed directly in the liver.

The trial will evaluate delivering a precisely controlled dose of vandetanib, an inhibitor of multiple tumour growth pathways, directly to the arteries feeding a liver tumour by pre-loading the drug on a radiopaque bead which can be visualised on CT scans. Although still at a very early stage of research, the development programme aims to improve current treatments for patients with primary liver cancer and metastatic colorectal cancer (mCRC).

The current standard of care for liver cancer patients is known as transarterial chemoembolisation, or TACE, and involves injecting beads through an artery using a microcatheter to block the tumour-feeding blood vessels, starving the tumour of oxygen and nutrients. These beads are usually loaded with a chemotherapy drug that is released over time directly at the tumour site, avoiding exposure to the rest of the body and reducing side effects. Despite advances in this procedure, liver cancer remains one of the most common causes of cancer death worldwide.1

To improve the treatment of patients with primary liver cancer and mCRC, the beads used in the VEROnA study (vandetanib-eluting radiopaque beads in patients with resectable liver malignancies) are pre-loaded with a multi-kinase inhibitor called vandetanib. Vandetanib targets genetic alterations and cell-signalling pathways that lead to liver cancer growth, recurrence and metastasis. These pathways, including vascular endothelial growth factors (VEGF-A and C) and epidermal growth factor receptor (EGFR), stimulate new tumour blood and lymph vessel growth and aid the development of solid tumours. They may also promote spread of the cancer to other organs and inhibit the body’s own immune response to the tumour. A phase II trial of vandetanib in patients with advanced liver cancer showed some promise,2 and provided a strong rationale for the loco-regional delivery of this drug.

Professor Ricky Sharma, Chair of Radiation Oncology at University College London and the study’s primary investigator, said: “The incidence and mortality rates for primary liver cancer continue to climb and it is vital that we explore new treatment approaches. This research is exciting because it is the first time we have been able to pre-load a targeted cancer drug on to an imageable bead, to deliver the targeted drug in high doses to the cancer and see exactly how well the beads reach the target we have defined.  By refining the treatment using information from this clinical trial, we may be able to develop a liver-directed treatment as a superior alternative to the rather poorly tolerated drug treatments we currently offer patients with this type of cancer.”

The vandetanib-eluting bead was developed in collaboration with Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland and Dr. Alban Denys, professor at the department of medical radiology at CHUV. Vandetanib-eluting beads use BTG’s recently developed radiopaque bead platform.3 Beads that can be visualised with CT or fluoroscopic imaging offer the advantage of providing visible confirmation of bead location during and after the embolisation procedure, enabling real-time adjustments to optimise patient treatment.4

Melanie Lee, Chief Scientific Officer at BTG said: “As leaders in Interventional Oncology, we are continuing to pursue better solutions for patients through innovation. Our suite of products are used to treat different stage cancers and they are delivered into the cancer tumour in a very targeted way, an approach called loco-regional therapy. This programme is at a very early stage of research, but testing vandetanib-eluting beads in man is an exciting milestone. Bringing to market the first embolic beads visible under X-ray imaging has enabled increased control and precision during treatment, and adding a targeted anti-cancer agent we may be able to offer a new option for hard to treat cancers in the liver.”

The VEROnA study is sponsored by BTG and supported by the Cancer Research UK Experimental Cancer Medicines Centre and the UCL Cancer Institute and the National Institute for Health Research University College London Hospitals Biomedical Research Centre.  Patients with primary liver cancer or mCRC who meet the eligibility criteria will be offered participation in the clinical trial at University College London Hospitals NHS Foundation Trust and the Royal Free Hospital NHS Foundation Trust.  Patients suitable for the VEROnA study are those scheduled to have their liver tumours removed surgically. By studying the resected tissue in great detail, and comparing it to the scans performed before the operation, researchers will be able to assess exactly where the vandetanib-eluting beads have been deposited in and around the tumours, and how much drug has been delivered to the target. In this way, the VEROnA “window of opportunity” clinical trial will assess the safety and tolerability of the new treatment and the potential it offers for treating liver cancer.


Common acid reflux medications promote chronic liver disease

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Researchers have discovered evidence that stomach acid suppression alters specific gut bacteria in a way that promotes liver injury and progression of three types of chronic liver disease.

Researchers have discovered evidence in mice and humans that stomach acid suppression alters specific gut bacteria in a way that promotes liver injury and progression of three types of chronic liver disease.

Approximately 10 percent of the general population take a proton pump inhibitor (PPI) drug to block stomach acid secretions and relieve symptoms of frequent heartburn, acid reflux and gastroesophageal reflux disease. That percentage can be as much as seven times higher for people with chronic liver disease.

“Our stomachs produce gastric acid to kill ingested microbes, and taking a medication to suppress gastric acid secretion can change the composition of the gut microbiome,” said senior author Dr Bernd Schnabl, Associate Professor of Gastroenterology at UC San Diego School of Medicine. “Since we found previously that the gut microbiome — the communities of bacteria and other microbes living there — can influence liver disease risk, we wondered what effect gastric acid suppression might have on the progression of chronic liver disease. We found that the absence of gastric acid promotes the growth of Enterococcus bacteria in the intestines and translocation to the liver, where they exacerbate inflammation and worsen chronic liver disease.”

To determine the effect of gastric acid suppression on the progression of chronic liver disease, Dr Schnabl’s team looked at mouse models that mimic alcoholic liver disease, NAFLD and NASH in humans. In each, they blocked gastric acid production either by genetic engineering or with a PPI (omeprazole/Prilosec). They sequenced microbe-specific genes collected from the animals’ stool to determine the gut microbiome makeup of each mouse type, with or without blocked gastric acid production.

The researchers found that mice with gastric acid suppression developed alterations in their gut microbiomes. Specifically, they had more Enterococcus species of bacteria. These changes promoted liver inflammation and liver injury, increasing the progression of all three types of liver disease in the mice: alcohol-induced liver disease, NAFLD and NASH.

To confirm it was the increased Enterococcus that exacerbated chronic liver disease, Dr Schnabl’s team also colonised mice with the common gut bacteria Enterococcus faecalis to mimic the overgrowth of intestinal enterococci they had observed following gastric acid suppression. They found that increased Enterococcus alone was sufficient to induce mild steatosis and increase alcohol-induced liver disease in mice.

The team also examined the link between PPI usage and alcoholic liver disease among people who abuse alcohol. They analyzed a cohort of 4,830 patients with a diagnosis of chronic alcohol abuse — 1,024 (21 percent) were active PPI users, 745 (15 percent) were previous users and 3061 (63 percent) had never used PPIs.

The researchers noted that PPI intake among these patients increased stool concentrations of Enterococcus. What’s more, the 10-year risk of a diagnosis of the alcoholic liver disease was 20.7 percent for active users of PPIs, 16.1 percent for previous users and 12.4 percent for never users. In other words, the rate of liver disease in people who chronically abuse alcohol was 8.3 percent higher for those who actively use PPIs compared to those who never used the acid-blocking medications.

The researchers concluded that there is an association between PPI use among people who abuse alcohol and risk of liver disease. However, they can’t yet rule out the possibility that there could be other unidentified factors that differ between patients that do and do not take PPIs, which might confound the relationship between PPI use and liver disease.

While this study relies upon mouse models and a patient database, and a large, randomized, controlled clinical trial would be needed to definitively show causality between PPI usage and risk of chronic liver disease in humans, Dr Schnabl said the initial data should at least get people thinking about reducing their use of PPIs in cases where they aren’t a necessity.

There are inexpensive and readily available alternatives to PPIs. However, even non-PPI-based antacids (e.g., Pepto-Bismol, Tums, or H2 blockers such as Tagamet and Zantac) still suppress gastric acid to a lesser degree. While these other types of antacids were not tested in this study, Dr Schnabl said any medication that suppresses gastric acid effectively could cause changes in gut bacteria and thus potentially affect the progression of chronic liver disease. Alternatively, non-pharmacological methods for managing heartburn are an option for some patients, including losing weight and reducing intake of alcohol, caffeine, and fatty and spicy foods.

“Our findings indicate that the recent rise in the use of gastric acid-suppressing medications might have contributed to the increased incidence of chronic liver disease,” Dr Schnabl said. “Although obesity and alcohol use predispose a person to acid reflux requiring antacid medication, many patients with chronic liver disease take gastric acid suppressive medications without an appropriate indication. We believe clinicians should consider withholding medications that suppress gastric acid unless there is a strong medical indication.”

This new information might also provide a new therapeutic avenue researchers could explore as a means to reduce the risk of liver injury in some people.

“We might someday be able to manipulate the gut microbiome, and in particular Enterococcus faecalis, to attenuate alcohol-related liver disease associated with gastric acid suppression,” Dr Schnabl said.


Allergan posts disappointing data in NASH

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It was only last year that Allergan decided to cough up $1.7 billion to acquire Tobira Therapeutics, with the main driver being its lead candidate for NASH, cenicriviroc (CVC).

It was a deal that raised a few eyebrows at the time, with the company having just released mixed data on the drug trials but it professed the drug’s strength in reducing fibrosis.

Allergan should then not be surprised to have found itself in a similar position after its latest Phase IIb trial. The treatment spectacularly missed its primary endpoint of a one-stage drop in patients’ disease score alongside the stabilisation of symptoms, with the treatment showing no benefit over placebo.

It left Allergan, similarly to Tobira before it, pointing towards a reduction in fibrosis in a certain subset of patients to recover the results of the trial. It highlighted data showing patients whose condition had worsened over the course of one-year placebo treatment showed some benefit, with 20% of patients receiving CVC, against 13% in placebo, achieving the combined endpoint of reduction in fibrosis by  at least one stage with no worsening of NASH.

“These data confirm the safety profile and anti-fibrotic effect of CVC after one year of treatment. Allergan is committed to advancing our portfolio of NASH treatment programs. We have gained important insights from this analysis which will further support our progress with CVC. The CENTAUR trial is a first of its kind with three biopsies in patients with NASH disease and liver fibrosis. It will help us greatly understand the natural history of NASH and help bring much needed treatment options to patients,” said David Nicholson, Chief Research & Development Officer, Allergan.

There is also potential for the treatment as part of a combination treatment, with a deal already having been struck with Novartis for its use alongside LJN452 as a treatment for NASH. This could be where the drug stands to benefit patients most, after such shaky Phase 2 data.

However, Allergan is already moved ahead with a Phase 3 trial of the drug, as it has already begun recruitment into the possibility of using the drug for liver fibrosis in adults with NASH. There will be serious questions raised regarding Allergan’s judgement if this trial also fails to hit its endpoints.