Boehringer Ingelheim announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to nintedanib for the treatment of systemic sclerosis with associated interstitial lung disease (SSc-ILD). The FDA’s Fast Track designation facilitates the development of new therapies that treat serious conditions and fulfill an unmet medical need in an effort to get treatments to those in need sooner.

This designation is based on Boehringer Ingelheim’s Investigational New Drug application (IND) of nintedanib for the treatment of SSc-ILD and the anticipated efficacy and safety data from SENSCIS™ (Safety and Efficacy of Nintedanib in Systemic SClerosIS), a double-blind, randomized, placebo-controlled global Phase III trial. This pivotal study is fully enrolled, including more than 520 patients from 32 countries.

“This Fast Track designation is an encouraging step in our ongoing research and commitment to advancing care of those with systemic sclerosis with interstitial lung disease,” said Christopher Corsico, M.D., Chief Medical Officer, Boehringer Ingelheim. “It is critical that we address the significant unmet medical need of those living with this disease and we are looking forward to working with the FDA to advance the development of this potential therapy.”

Annelise Rønnow, president of FESCA (The Federation of European Scleroderma Associations), added: “There are only very few drugs assessed in clinical trials for scleroderma with lung involvement – a devastating reality for people living with the disease. We appreciate that the FDA recognised the importance of the development in this field.”

Systemic sclerosis, also known as scleroderma, is a rare disease characterized by the thickening and scarring of connective tissue of multiple organs in the body, typically affecting women between ages 25 and 55.(1,2) Most people with the disease will develop some degree of lung scarring, or interstitial lung disease (ILD), which is the leading cause of death among people with systemic sclerosis.(3-6)

Nintedanib, which is marketed as OFEV®, is approved for a rare lung disease called idiopathic pulmonary fibrosis, or IPF, and has been shown to slow disease progression as measured by annual rate of decline in lung function. Because SSc-ILD and IPF share similarities in how the underlying lung scarring, or fibrosis, forms in people with the disease, Boehringer Ingelheim is evaluating the impact of nintedanib on SSc-ILD.

About SENSCIS™

SENSCIS™ is a randomized, double-blind, placebo-controlled study (NCT 02597933) evaluating the efficacy and safety of nintedanib 150 mg twice daily over 52 weeks up to a maximum of 100 weeks in people with SSc-ILD. The primary endpoint is the annual rate of decline in forced vital capacity (FVC), a measure of lung disease progression. Key secondary endpoints include the absolute change from baseline in the modified Rodnan Skin Score (mRSS), which is an evaluation of people’s skin thickness, and the absolute change from baseline in the Saint George’s Respiratory Questionnaire (SGRQ) total score, which measures the health-related quality of life of people with lung diseases.

About Boehringer Ingelheim

Innovative medicines for people and animals have, for more than 130 years, been what the research-driven pharmaceutical company Boehringer Ingelheim stands for. Boehringer Ingelheim is one of the pharmaceutical industry’s top 20 companies and to this day remains family-owned. Day-by-day, some 50,000 employees create value through innovation for the three business areas; human pharmaceuticals, animal health and biopharmaceutical contract manufacturing. In 2016, Boehringer Ingelheim achieved net sales of around 15.9 billion euros. With more than three billion euros, R&D expenditure corresponds to 19.6 per cent of net sales.

Social responsibility comes naturally to Boehringer Ingelheim. That is why the company is involved in social projects such as the “Making More Health” initiative. Boehringer Ingelheim also actively promotes workforce diversity and benefits from its employees’ different experiences and skills. Furthermore, the focus is on environmental protection and sustainability in everything the company does.

1. Scleroderma Foundation. What is scleroderma? Available at: www.scleroderma.org/site/PageNavigator/patients_whatis.html#.V hgSaPlViko. Last accessed January 2018.
2. Herzog EL, et. al. Review: Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis: How Similar and Distinct? Arthritis Rheum. 2014;66:1967-1978.
3. Solomon JJ, Olson A L, Fischer A, et al. European Respiratory Update: Scleroderma lung disease. Eur.Respir. Rev. 2013; 22: 127, 6-19.
4. Schurawitzki H et al. Interstitual lung disease in progressive systemic sclerosis: High-resolution CT vs radiography. Radiography. 1990;176:755-9.
5. Steen V et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;66(60:1625-35.
6. Nihtyanova SI et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheum 2014;66(6):1625-35.

H. Lundbeck A/S (Lundbeck) and Prexton Therapeutics BV (Prexton) today announced signing of a definitive agreement in which Lundbeck will acquire Prexton. Under terms of the agreement, Lundbeck will pay EUR 100 million (approximately DKK 750 million) upfront and is furthermore required to later pay up to EUR 805 million (approximately DKK 6 billion) in development and sales milestones to the group of current owners.

By acquiring Prexton, Lundbeck will obtain global rights of an attractive compound (foliglurax) which currently is in clinical phase II testing for symptomatic treatment of OFF-time reduction in Parkinson’s disease and dyskinesia including Levodopa Induced Dyskinesia (LID). First data from the ongoing clinical phase II programme is expected to be available during the first half of 2019.

“By acquiring Prexton, Lundbeck will obtain global rights to foliglurax, an exciting first-in-class compound, and gain full control of the asset,” said Anders Götzsche, interim CEO and CFO at Lundbeck. “Foliglurax addresses high unmet needs with its potential indication in Parkinson’s fitting perfectly within Lundbeck’s core areas and this treatment option also appears to be highly interesting for patients, physicians and payors.”

Foliglurax works by stimulating a specific glutamatergic target (mGluR4) which activates a compensatory neuronal system in the brain which is largely unaffected in Parkinson’s disease. Animal models have convincingly demonstrated positive effects in models of Parkinson’s disease. The aim is to treat the motor symptoms of Parkinson’s disease, such as resting tremor, muscle rigidity and uncontrolled movements (dyskinesia).

Deal terms

Lundbeck will pay EUR 100 million upfront to the current investors of Prexton Therapeutics BV. Furthermore, Lundbeck is required to pay up to EUR 805 million in development, regulatory and sales milestones depending on successful outcome of certain undisclosed milestones. More than half of the EUR 805 million is connected to sales milestones.

About foliglurax

Foliglurax (PTX002331) is a small-molecule positive allosteric modulator of group III metabotropic glutamate receptor 4 (mGluR4 PAM), for the potential oral treatment of Parkinson’s disease.

A single- and multiple-ascending oral dose phase I trial (NCT02639221) in healthy volunteers with foliglurax was successfully completed in 2016. The results showed that foliglurax appears well-tolerated with a satisfactory pharmacokinetic (how the drug is processed in the body) profile.

In July 2017, Prexton initiated a phase II clinical trial (NCT03162874) with foliglurax. The trial will enroll around 165 Parkinson’s patients in sites across six European countries (U.K., Germany, France, Austria, Spain, and Italy). The double-blinded, randomized, placebo-controlled, parallel-arm study will assess the effectiveness, safety, and tolerability of foliglurax in reducing motor complications of levodopa therapy in patients experiencing end-of-dose wearing-off and levodopa-induced dyskinesia.

Two groups will receive oral doses (10 mg and 30 mg) of the treatment over 28 days, in addition to their standard medication, incl. levodopa. A third group will receive placebo. The primary outcome measure will be the change in the daily awake “OFF”-time (i.e. time where the treatment does not work) based on patient diary entries between the start and end of treatment. The study is expected to be completed in 2019.

About Parkinson’s disease

Parkinson’s is a devastating progressive neurological condition affecting around 6 million people worldwide. The disease is caused by the degeneration of dopaminergic brain cells. The main motor symptoms are resting tremor, muscle rigidity, and slowed movement (bradykinesia). Uncontrolled movements (dyskinesia) is a debilitating complication to levodopa use.

Current treatments aim to replace dopamine or to mimic its effects. Patients are administered with the dopamine precursor levodopa. This treatment provides adequate symptomatic relief initially, but over time, it loses efficacy as the disease progresses and patients experience serious debilitating, complications, such as increased OFF time and dyskinesia.

About Prexton

Prexton is a biopharmaceutical company founded in 2012 by Francois Conquet and M Ventures, the corporate venture arm of Merck KGaA, their entrepreneurial partnership program, which supports the creation of spin-offs from Merck. Prexton applies a new scientific approach that fully integrates molecular, behavioral and chemistry technologies to address Parkinson’s disease and other brain disorders. Prexton is based in Oss (The Netherlands) and in Geneva (Switzerland). Other major investors include Forbion, Seroba Life Sciences, Sunstone Capital and Ysios Capital.

About H. Lundbeck A/S

H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) is a global pharmaceutical company specialized in psychiatric and neurological disorders. For more than 70 years, we have been at the forefront of research within neuroscience. Our key areas of focus are Alzheimer’s disease, depression, Parkinson’s disease and schizophrenia.

Our approximately 5,000 employees in 55 countries are engaged in the entire value chain throughout research, development, manufacturing, marketing and sales. Our pipeline consists of several late-stage development programmes and our products are available in more than 100 countries. We have production facilities in Denmark, France and Italy. Lundbeck generated revenue of DKK 17.2 billion in 2017 (EUR 2.3 billion; USD 2.6 billion).

Approximately one sixth of clinical trials registered on both ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR) have discrepancies in their completion status, according to a study published March 7, 2018 in the open-access journal PLOS ONE by Jessica Fleminger and Ben Goldacre from the University of Oxford, UK.

Trial registries are important sources of information for clinicians and researchers, since they provide information on what trial results are pending or already available. While building OpenTrials, an open database that aims to link all publicly available information from all clinical trial registries, the authors of this study identified multiple errors, omissions and discrepancies between different registries. These differences prompted the researchers to investigate the prevalence of incorrect completion statuses between two major registries, the EU Clinical Trials Register (EUCTR) and ClinicalTrials.gov.

The researchers analyzed 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR, examining their trial completion status and reporting status for discrepancies. They found that 16.2% of dual registered trials had discrepant completion statuses and 33.9% of dual-registered trials listed as ‘ongoing’ on EUCTR were listed as ‘completed’ on ClinicalTrials.gov.

The researchers suggest that the prevalence of incorrect statuses on trial entries could mean that they are excluded from studies looking at publication bias or systematic reviews pooling together clinical data from different clinical trials. While it is unclear whether researchers, registry owners, or both are responsible for the errors, the authors recommend that researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that the completion status is accurate.

“Trial registries are important public documents: doctors, researchers, and patients rely on the information that trialists post about their clinical trial,” says Ben Goldacre. “Concerningly, we now show that this data is commonly inaccurate.”

Jessica Fleminger, Ben Goldacre.
Prevalence of clinical trial status discrepancies: A cross-sectional study of 10,492 trials registered on both ClinicalTrials.gov and the European Union Clinical Trials Register.
PLoS ONE 13(3): e0193088. doi: 10.1371/journal.pone.0193088.