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Vaccines Europe: vaccinatie als hoeksteen Europese gezondheidszorg

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In een recent verschenen manifest maant Vaccines Europe, de Europese koepel voor vaccinbedrijven, Europese beleidsmakers tot actie. De boodschap: om burgers optimaal te beschermen tegen vaccineerbare aandoeningen, moeten we het positieve momentum rond vaccinatie nú benutten. Een oproep die HollandBIO uit het hart gegrepen is. Nederland zette tijdens de Ronde Tafel en het recente Plenair Debat over vaccineren al zijn beste beentje voor op weg naar een optimale inzet van vaccins in de strijd tegen infectieziekten.

Het manifest van Vaccines Europe vat de visie en aanbevelingen samen van de innovatieve vaccin industrie in Europa. Het document gaat onder andere in op de noodzaak tot een levensloopbestendig vaccinatieprogramma, betere communicatie via zorgprofessionals, het R&D klimaat en de samenwerking tussen (internationale) stakeholders. Om de samenwerking rond vaccineerbare aandoeningen te verbeteren nam de Europese Commissie in december vorig jaar ook al het voortouw. Zij nam met unanieme steun deze Raadsaanbeveling aan.

Ook uit de Nederlandse activiteiten rondom vaccinatie spreekt urgentie. In januari vond in de Tweede Kamer een ronde tafel over vaccineren plaats. Nog geen maand later was er tijd voor een plenair debat, waarin Kamerleden staatssecretaris Blokhuis bevroegen over zijn vaccinatiebeleid. Uit de diverse toezeggingen van de Staatssecretaris en ingestemde moties blijkt een absolute bereidheid om werk te maken van vaccinatie in Nederland.

De Europese en Nederlandse ontwikkelingen stemmen hoopvol. HollandBIO blijft pleiten voor een optimale benutting van vaccins – zowel binnen als buiten de vaccinatieprogramma’s. Want wij zijn pas tevreden als de aanbevelingen uit onze position paper “nog verder met vaccineren” gerealiseerd zijn.

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Driewerf hoera voor Biogen!

En weer springt biofarmaceut Biogen in de bres voor patiënten. Dankzij het bedrijf krijgen MS-patiënten tijdelijk een aanzienlijk deel van de aanschafkosten van het geneesmiddel Fampyra terug, in afwachting van een herbeoordeling van de effectiviteit van het middel door het Zorginstituut. Het instituut beoordeelde de effectiviteit van het middel recent als onvoldoende bewezen, waarop patiënten en artsen massaal de noodklok luidden. En terecht, want zonder vergoeding is het middel voor veel MS-patiënten onbereikbaar, terwijl Fampyra voor een groep wel degelijk het verschil maakt tussen lopen of rolstoel. In een persbericht laat Minister Bruins voor Medische Zorg en Sport weten “Biogen erkentelijk te zijn voor hun constructieve opstelling” en dat Biogen zijn maatschappelijke verantwoordelijkheid neemt. En dat mag ook wel eens gezegd worden! Het volledige bericht van VWS lees je hier.

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Wat komt er na QALY?

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Wat mag een extra levensjaar kosten? Die vraag leidde jaren geleden tot het omstreden bedrag van tachtigduizend euro per QALY: de maximumprijs voor één levensjaar in goede gezondheid. Vandaag de dag hanteert het Zorginstituut tachtigduizend euro per QALY als grens voor kosteneffectieve zorg.

Toch vragen én betalen we soms meer voor weesgeneesmiddelen. Terecht of niet? Verdienen geneesmiddelen voor zeldzame aandoeningen coulance? Zijn er alternatieve modellen of uitgangspunten om deze medicijnen en therapieën op maat toegankelijk te houden? Hoog tijd voor een goed gesprek. Tijdens het Rare Disease Symposium presenteren Marc Pomp (gezondheidseconoom), Tim Kanters (IMTA) en Eelko den Breejen (BIOGEN), onder leiding van Patrick Ooms (KWF), hun oplossingen. Zorg dat je erbij bent! Lees meer over het Symposium of registreer je direct.

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Input gevraagd! Consultatie modernisering geneesmiddelenvergoedingssysteem (GVS)

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HollandBIO is uitgenodigd voor deelname aan een door het ministerie van VWS georganiseerde consultatiebijeenkomst over de modernisering van het Geneesmiddelenvergoedingssysteem (GVS). Een mooie kans om HollandBIO’s visie onder de aandacht te brengen en eventuele knelpunten op de route van lab naar patiënt weg te nemen.

Om onze positie te bepalen, hebben wij de hulp van onze leden nodig. We hebben daarom een korte enquête opgesteld om jouw ervaring met en wensen voor het GVS te polsen. Het invullen van de enquête neemt niet meer dan 10 minuten in beslag. Klik hier om de enquête in te vullen.

Vanaf maandag 18 maart gaan wij de antwoorden uitwerken. We nemen jouw input graag mee!

Achtergrondinformatie modernisering GVS

De Minister voor Medische Zorg en Sport heeft in de zomer van 2018 het voornemen aangekondigd het geneesmiddelenvergoedingssysteem (GVS) te moderniseren en toekomstbestendig te maken. Hiertoe analyseert een projectgroep van VWS, het Zorginstituut en CIBG de werking en de effecten van het GVS. Ook onderzoekt zij verschillende oplossingsrichtingen. De voortgangsbrief geneesmiddelenbeleid aan de Tweede Kamer van afgelopen 20 december zet in alinea “1.2 Geneesmiddelenvergoedingssysteem” (pagina 5 van 27) de stand van zaken uiteen over de modernisering van het GVS. 

Samenvattend noemt de Minister drie knelpunten:       

  1. In bepaalde gevallen treedt er geen of beperkte prijsdruk op;
  2. Er kunnen knelpunten voor patiënten optreden, bijvoorbeeld omdat fabrikant een geneesmiddel niet meer aanbiedt, omdat vergoedingslimiet binnen GVS te laag is. Maar ook wanneer het voor patiënten niet mogelijk is om te wisselen naar een geneesmiddel zonder bijbetaling;
  3. Beperkte beoordelingscapaciteit van het Zorginstituut.

Het komende jaar vindt verdere kwantificering en toetsing van de knelpunten plaats en onderzoekt de projectgroep hoe de knelpunten het beste aangepakt kunnen worden. Er zijn twee scenario’s om oplossingen door te voeren:

  1. GVS in stand houden en maatregelen binnen het systeem doorvoeren om knelpunten op te lossen;
  2. Alternatief systeem om de betaalbaarheid en toegankelijkheid van de geneesmiddelenvoorziening zo goed mogelijk te realiseren.
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Alnylam Reports Positive Topline Results from Phase 3 Study in Acute Hepatic Porphyria

Alnylam, the leading RNAi therapeutics company, announced today that the ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP), met its primary efficacy endpoint and the majority of secondary endpoints. Specifically, givosiran met the primary endpoint of reduction in the annualized rate of composite porphyria attacks relative to placebo (p less than 0.00000001) and achieved statistically significant results for five of nine secondary endpoints (p less than 0.0001), with a safety and tolerability profile that the Company believes is encouraging, especially in this high unmet disease. Based on these results, the Company plans to complete its rolling submission of a New Drug Application (NDA) and file a Marketing Authorisation Application (MAA) in mid-2019.

“Patients living with AHP experience debilitating and sometimes life-threatening neurovisceral attacks as well as chronic disease manifestations which negatively impact their quality of life. We believe the ENVISION results demonstrate a robust therapeutic benefit of givosiran treatment on the debilitating aspects of this disease. Based on these results, we believe givosiran has the potential, if approved, to be a transformative medicine for AHP patients and their families,” said Akshay Vaishnaw, M.D., Ph.D., President, R&D at Alnylam. “We extend our profound thanks to all the patients, investigators, and study staff who participated in the ENVISION study.”

“These positive ENVISION results represent another landmark event in Alnylam’s pioneering efforts to advance RNAi therapeutics as a whole new class of medicines. Notably, givosiran is the first GalNAc-conjugate siRNA to achieve positive Phase 3 results, and the second example of Alnylam’s R&D strategy bearing fruit due to our focus on genetically validated targets for the advancement of potential high impact medicines,” said John Maraganore, Ph.D., CEO of Alnylam. “Assuming favorable regulatory review, we very much look forward to adding givosiran as the second product in our global commercialization efforts. Indeed, we believe today’s news brings us one important step closer to meeting our Alnylam 2020 goals of building a multi-product, global commercial company with a deep clinical pipeline for continued growth and a robust product engine for sustainable innovation.”

Givosiran has received Breakthrough Therapy and Prime designation by the FDA and EMA, respectively, and has Orphan Drug status in the U.S. and EU for the treatment of AHP. The Phase 1 results of givosiran were recently published in The New England Journal of Medicine1. FullENVISION study results will be presented in an oral plenary session on Saturday, April 13 at EASL in Vienna, Austria. The ENVISION results have not yet been reviewed by regulatory authorities.

ENVISION Study Results

ENVISION, a randomized, double-blind, placebo-controlled trial, enrolled 94 patients with AHP (including 89 with genetically-confirmed acute intermittent porphyria [AIP], the most common subtype of AHP), at 36 study sites in 18 countries around the world, and is the largest ever interventional study conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. The primary endpoint for the study was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with AIP over six months.

At six months, givosiran met the primary endpoint in patients with AIP (p less than 0.00000001). All the components of the composite primary endpoint and all subgroup analyses for the primary endpoint favored givosiran. Secondary endpoints listed below also demonstrated statistically significant favorable differences in the givosiran arm compared to placebo (p less than 0.0001):

  • Urinary ALA levels at three months in AIP patients;
  • Urinary ALA levels at six months in AIP patients;
  • Urinary PBG levels at six months in AIP patients;
  • Annualized days of administered hemin doses in AIP patients; and
  • Annualized attack rate in patients with AHP (including AIP).

The remaining four secondary endpoints did not meet the hierarchical threshold for significance and included: daily worst pain (p equal to 0.053), daily worst fatigue (p equal to 0.29), daily worst nausea (p equal to 0.25), and the physical component summary of the SF-12 health survey in AIP patients (p equal to 0.022).

Adverse events (AEs) were reported in 43/48 (89.6 percent) of givosiran and 37/46 (80.4 percent) of placebo patients and serious adverse events (SAEs) were reported in 10/48 (20.8 percent) of givosiran and 4/46 (8.7 percent) of placebo patients. There were no deaths in the study. One patient, described below, in the givosiran arm (2.1 percent) discontinued treatment due to an AE. AEs reported in greater than 10 percent of givosiran patients and seen more frequently compared to placebo were: nausea, injection site reactions, chronic kidney disease and fatigue; those reported in greater than 10 percent of placebo patients and seen more frequently than in givosiran-treated patients were headache, urinary tract infection, vomiting and pyrexia. The AEs of chronic kidney disease were reported in five givosiran-treated patients (10.4 percent) and no placebo patients; these events were all in patients with renal dysfunction at baseline and patients continued dosing throughout the study. Liver transaminase increases greater than three times upper limit of normal (ULN) were observed in 7/48 (14.6 percent) patients on givosiran and 1/46 (2.2 percent) patients on placebo; all had evidence of iron overload or liver disease at baseline. As previously reported and as noted above, one patient on givosiran discontinued treatment due to an increase in alanine aminotransferase (ALT) levels greater than 8 times ULN, a protocol-defined stopping rule; this elevation did not meet Hy’s Law and subsequently resolved. Peak ALT levels in the other six givosiran-treated patients ranged from 3.0-5.4 times ULN and were not accompanied by bilirubin increases. The patients were asymptomatic, and all events resolved with continued dosing (n=5) or after a brief pause in dosing (n=1).

Upon completion of dosing in the ENVISION double-blind period, all eligible patients (93/94 or 99 percent) enrolled in the ENVISION open-label extension (OLE) study, receiving monthly givosiran administration. In addition, patients continue dosing in the Phase 1/2 OLE study with over two years of exposure to givosiran.

Source: Alnylam

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Virtuvax Reports Positive First-in-Human Results of Nasal Spray RSV Vaccine

Virtuvax and the trustee of biotech company Mucosis, Mr. Holtz LLM announced the results of a first-in-human study of the intranasal Respiratory Syncytial Virus (RSV) vaccine candidate, SynGEM. The study was executed by Imperial College London.

Results of the study have been posted (in press) on the website of the American Journal of Respiratory and Critical Care Medicine. The vaccine was found to be safe and immunogenic in healthy adults.

“Virus-specific immunogenicity induced after SynGEM vaccination was demonstrated by systemic IgG+ and IgA+ responses in terms of antibody-secreting cells (ASCs)” indicated prof. Openshaw, professor of Experimental Medicine at Imperial College London. Professor Openshaw added that “SynGEM induced some RSV-specific mucosal IgA in most individuals, particularly in those with low pre-existing F-specific IgA titers. Indeed, higher doses of the vaccine induced prolonged IgA-producing ASC responses in some volunteers.” Prof. Openshaw further explained that “The publication includes in vitro data supporting the clinical observations, showing that SynGEM induces a dose-dependent antibody response associated with cytokine production from T-helper cells.”

Dr. Chiu, principal investigator of the clinical trial, commented: “Previously, we showed that antibodies induced by natural RSV infection were only short-lived and we hypothesized that RSV-induced immunomodulatory mechanisms impaired the antibody responses against the virus. In this study, SynGEM not only induced immune responses but also boosted long-term systemic RSV-specific antibodies for at least 6 months. Vaccination with the SynGEM RSV vaccine therefore was not associated with evidence of immune modulation, as seen after infection with live RSV.”

In another publication also in AJRCCM, senior author Prof. Louis Bont of University Medical Center Utrecht, The Netherlands commented on the SynGEM trial. Prof. Bont argued that in the absence of a correlate of protection to RSV, vaccine developers are working in the dark. In the case of SynGEM, preclinical data had shown protection against infection suggesting evidence of the vaccine providing protective immunity. However, despite the induction of broad immune responses, neutralizing antibodies were not detected in the clinical trial. In their comment, the authors suggested that testing of the SynGEM vaccine in a human challenge model might be a quick way to finally determine proof of concept of efficacy.

The investigators of Imperial College were surprised that no detectable neutralizing antibody responses were found, since extensive stability tests had shown stable binding of such antibodies by SynGEM. Openshaw said: “the system needs further optimization, but establishes proof of principal that the nasal vaccine approach can work. It was a shame that the programme was ended before the infection challenge component could be performed”. Trustee of Mucosis, Mr. Holtz, commented: “During the clinical trial, Mucosis was confronted with a sudden shortage of finances and the company had to apply for bankruptcy before the final results were known as published today. Since these long-term data have become available as of now, any further development of the vaccine may be taken forward by other companies interested in doing so.”

SynGEM is based on a unique pre-fusion version of the F subunit of RSV, shown to raise more potent serum neutralizing antibodies against RSV compared with the post-fusion F antigen approach others have used. The pre-fusion conformation (pre-F), which predominates on infectious virions, displays a

distinct antigenic site (site Ø) preferentially targeted by the most potent neutralizing antibodies. Preclinical studies using SynGEM showed induction of high levels of both systemic and mucosal antibodies.

Delivered via the mucous membranes in the nose, the vaccine candidate is also able to recruit antibodies produced in the mucosal linings of the body, with the potential to effectively stop the virus from entering the body via the mucosal pathways, where over 90% of pathogens enter the body.

SynGEM is based on Mucosis’ patented Mimopath technology, which uses bacterium-like particles (BLP) derived from food-grade bacteria, to deliver the antigen in a more natural conformation and boost the body’s immune response to the virus.

RSV is a common contagious infection of the lungs and respiratory pathways, eliciting cold-like symptoms in adults. Whilst RSV infection is normally mild in healthy adults, the infection can lead to serious and sometimes fatal diseases such as pneumonia and bronchiolitis, most often in susceptible populations such as the young and elderly. Every year in the US, RSV infections lead to 57,527 hospitalizations of children under 5 year’s old (2)and are responsible for up to 200,000 deaths annually worldwide (3). The annual global burden of RSV illness is significant, with 33.8 million estimated new episodes of RSV-associated acute lower respiratory infection (ALRI) worldwide in children under 5, and over 3.4 million hospital admissions associated with severe RSV disease. Global mortality was estimated at 253,500 deaths in 2010.

The Wellcome Trust translational fund supported the clinical trial of SynGEM with a staged award of up to €3.44 million (£2.77 million).

Source Virtuvax

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BiosanaPharma gets approval to start phase I clinical trial for a biosimilar version of omalizumab

BiosanaPharma has received permission from the Australian Bellberry Human Research Ethics Committee HREC to start a phase I clinical trial of their first pipeline product. The trial consists of a bioequivalence double-blind, randomized, two-parallel-group phase I study of a humanized anti-immunoglobulin E monoclonal antibody ‘BP001’ as lyophilized powder formulation compared with the standard omalizumab (Xolair®) lyophilized powder formulation in healthy male volunteers. Prior to the submission of the Investigative Brochure to the HREC an extensive comparability exercise was performed between BP001 and Xolair®, indicating functional, binding and structural similarity between the two molecules. This extensive laboratory exercise was also sufficient for Biosana to obtain a waiver for preclinical studies in animal models from the EMA.

The Phase I trial is expected to be concluded and fully reported in Q4 2019.

Ard Tijsterman, CEO of BiosanaPharma: “We are extremely happy and proud that we’ve been able to develop our first biosimilar product, produced by our innovative ‘3C process’, the first fully continuous process to deliver a product entering phase I. We will start negotiations with potential marketing & sales partners now to perform phase III studies and secure future global distribution of the product.”

Omalizumab

Omalizumab is marketed by Roche/Genentech (USA) and Novartis (ROW) as Xolair® since 2006. It is used to treat moderate to severe allergic asthma and chronic idiopathic urticaria in patients aged 12 years and above in the US and the EU. Additionally, it is approved for paediatric patients aged 6 to 11 years in the EU. Xolair® is delivered via subcutaneous injections. Total sales for Xolair® in 2018 were US$ 2.9M with a consistent growth in both indications of 11-13% annually.  The US market accounted for roughly 2/3 of total Xolair® sales. The patent on Xolair® has expired in 2017 in the US and Europe (Novartis, 2016).

BiosanaPharma

BiosanaPharma is a Dutch/Australian biotechnology company with a disruptive approach to the manufacture and delivery of monoclonal antibody therapeutics (mAbs). BiosanaPharma’s “3C process” offers a 90% reduction in the cost of developing and manufacturing EMA/FDA quality mAbs. The 3C process is a fully-continuous, small footprint platform and produced BiosanaPharma’s first pipeline drug BP001, now approved to enter Phase I (see above).

BiosanaPharma is also developing a platform for oral delivery of biologicals, which has delivered successful preclinical results. The current pipeline consists of biosimilars and oral versions of blockbuster biologics.

Source: BiosanaPharma

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Kidney-on-a-Chip in Nature Biotechnology

Scientists from the Hubrecht Institute, the University of Utrecht, and MIMETAS have successfully grown kidney tubules derived from human kidney adult stem cells in microfluidic chips. This research has been published in Nature Biotechnology by the world-leading research group from Professor Hans Clevers.

Henriette Lanz, Ph.D., Director of Biology at MIMETAS and co-author on the paper explains: “Scientists at the Hubrecht Institute managed to reprogram stem cells found in the human kidney cortex to cells that are similar to tubular cells of the kidney. From these cells, my team has grown three-dimensional perfused kidney tubules. We have discovered that these tubules are fully polarized, meaning that they distinguish inside from outside, just like in a real kidney. Moreover, the biologically important barrier function of the kidney tubes is intact. We show that transporter activity is functional, which is a hallmark of kidney tissue, responsible for pumping of nutrients and toxicants across the kidney barrier. We can grow 40 of such tubules in one single OrganoPlate®. The kidney tubes can be used to create disease models that allow the development of novel therapies. This novel technology offers a powerful human alternative to animal testing for toxic side effects of new medicines.”

A mini kidney from the lab doesn’t look like a normal kidney, but the simple cell structures share many of the characteristics of real kidneys. Researchers can use them to study certain kidney diseases. “We can use these mini kidneys to model various disorders: hereditary kidney diseases, infections, and cancer. This allows us to study in detail what exactly is going wrong”, says Hans Clevers, Professor of Molecular Genetics at Utrecht University and the University Medical Center Utrecht, and group leader at the Hubrecht Institute.“This helps us to understand the workings of healthy kidneys better, and hopefully, in the future, we will be able to develop treatments for kidney disorders.”

Read the full Nature paper here: https://www.nature.com/articles/s41587-019-0048-8

Source: MIMETASand Hubrecht institute

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Gezondheidsraad: varen op wetenschap

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Met een interview in haar nieuwsbrief Graadmeter mengt ook de Gezondheidsraad (GR) zich in het maatschappelijk en politiek debat over vaccineren. Prof. Gerhard Zielhuis, voorzitter van de Commissie Vaccinaties, licht in dit interview onder andere het beoordelingskader en de rol van de GR omtrent de dalende vaccinatiegraad toe. HollandBIO vindt het top dat ook de GR, als wetenschappelijke hoeder van onder meer het Rijksvaccinatieprogramma, zich nu in de discussie mengt.

Het interview sluit mooi aan op het plenaire debat over vaccinatie in de Tweede Kamer, twee weken geleden. Middels een motie droeg de Kamer Staatssecretaris Blokhuis op om geregistreerde vaccins direct te voorzien van een advies over opname in een programma. Een oproep die bij HollandBIO met gejuich ontvangen werd. De Staatssecretaris is nu aan zet.

HollandBIO is van mening dat ook vaccins die (nog) niet voldoen aan de criteria voor opname in een vaccinatieprogramma of het verzekerd pakket, een route op maat verdienen. Nu belanden die vaccins vaak ongebruikt op de plank, al voegen ze op individueel niveau nog zoveel waarde toe. Hierdoor blijft gezondheidswinst liggen. HollandBIO is pas tevreden als hier een oplossing voor komt en we vaccins optimaal benutten in de strijd tegen infectieziekten.

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Dure medicijnen: wat klopt er van de argumenten van de farmaceutische industrie?

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Afgelopen week publiceerde de Volkskrant een verfrissend gebalanceerd artikel over de totstandkoming van geneesmiddelprijzen. Zeven argumenten van de sector om die prijzen te verklaren passeren hierin de revue. Biogen en Roche grepen deze kans aan en gingen open en eerlijk het gesprek aan over de complexiteit van en uitdagingen in de ontwikkeling en prijsstelling van geneesmiddelen. Een dikke pluim voor Biogen, Roche én de Volkskrant. HollandBIO hoopt dat dit goede voorbeeld breed navolging krijgt. Voor nu: een absolute must-read!

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