Humabs BioMed SA, a leading Swiss antibody therapeutics company, today announced that it has received a milestone payment from its licensing agreement with Novartis. In 2009, Humabs and Novartis entered into an exclusive licensing agreement for the use of selective human monoclonal antibodies discovered by Humabs’ proprietary Cellclone technology. A Novartis program based on this technology has entered into phase II clinical trials in the U.S. and Germany, triggering the payment.
“We are very pleased about reaching this important milestone,” said Alcide Barberis, CEO of Humabs BioMed. “This underlines the value of our platform, which is not just selecting for binders to pre-defined targets, but uses a functional, target-agnostic approach.”
Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) this year put out several negative assessments of newly introduced drugs, stating the data did not prove “additional benefit” over existing treatments. In all cases, IQWiG came to the conclusion after deviating from the study design the companies had discussed with the regulators. Instead, IQWiG’s experts divided the patient population into subgroups, saying those subgroups needed different comparator treatments. As a result, these data were either not available or the subgroups were too small to demonstrate statistical significance.
One example is Pfizer’s Xiapex injectable collagenase, approved in early 2011 to treat Dupuytren’s contracture. IQWiG stated that Xiapex does not provide an additional benefit to patients because “it was not possible to derive such additional benefit from the dossier and because the manufacturer did not provide additional or suitable data” to substantiate the claim.
While the manufacturer had compared the Xiapex injection to a surgical treatment, partial fasciectomy (PF), IQWiG for its assessment established six subgroups of patients according to the severity of the disease and chose three different treatment options as comparator: no therapy, percutaneous needle fasciectomy (PNF) and partial fasciectomy (PF). As a result, IQWiG was able to state that Pfizer did not provide evaluable data because the company’s selected comparators differed from IQWiG’s comparators for all but one patient subgroup.
In the case of Eisai’s breast cancer drug Halaven eribulin, IQWiG’s verdict ruled that it could not find evidence for eribulin resulting in a prolonged life expectancy. IQWiG added that Halaven might provide an overall survival benefit for patients for whom taxanes or anthracyclines are no longer an option, but it was unclear whether the benefit was significant. Again, the assessment was made by subdividing the patient group. IQWig defined two subpopulations – one for which an additional anthracycline or taxane treatment was thought to be an option and one for which this was not.
Eisai, in contrast, had compared Halaven to a “Treatment of Physician’s Choice” (TPC) as there are no established national or international treatment guidelines for a standard therapy of women with metastatic or locally advanced breast cancer after failure of two standard chemotherapies including an anthracycline or taxane. This design of Eisai’s EMBRACE was established in discussions with the European Medicine’s Agency (EMA). Being a European study, the participating physicians sometimes opted for therapies not approved in Germany – a reason for IQWiG to not include these data in its assessment. As a result, only 69% of the EMBRACE study patients were regarded as suitable for an assessment.
The same approach was taken in the assessment of Novartis’ Gilenya fingolimod, the first oral treatment for Multiple Sclerosis (MS) approved in 2011. IQWiG once again performed separate assessments of the drug in three groups of patients, choosing three different comparators. Following this operation, IQWiG was able to find data only for one of these subgroups in the study, not enough to establish an additional benefit with sufficient statistical significance. However, one of the comparisons chosen by IQWiG – fingolimod against glatiramer acetate in patients with relapsing/remitting MS – would have been impossible as fingolimod is approved as second-line therapy in this indication while there are no studies of glatiramer acetate differentiating between first-line and second-line treatments.
In all cases, manufacturers may respond to the assessment, after which the Federal Joint Committee (G-BA) will review IQWiG’s recommendation before making a final decision. If G-BA deviates from IQWiG’s negative assessment, the manufacturers have to negotiate the price with the Statutory Health Insurance Funds Association (GKV-Spitzenverband) under the AMNOG pricing scheme. If G-BA agrees with the IQWiG assessment that a drug has no clinical benefit beyond available treatments, the drug will be added to the reference pricing system, which gives the same base price to all comparable drugs in the respective therapeutic group.
Solar cells can become cheap bulk ware, even for developing countries, writes Manfred Lindinger in Frankfurter Allgemeine Zeitung (FAZ). He introduces a technology for printing a sheet of zinc oxide, a polymer containing fullerenes and an electrode made from polymers on paper. The technology developed at Technical University Chemnitz can use ordinary printing machines and paper, and the resulting solar paper can be bended and folded. However, the efficiency is still very poor (1.3% at 5 V compared to 10 or more with conventional ones). Life span will amount to a few months. For other approaches to make cheaper solar cells, see this post.
Martina Lenzen-Schulte, also in FAZ, explains how measle viruses leave cells to enter the airway. Today it is known that they do not proliferate in the outer epithelium cells but in lymph nodes. The way back is facilitated by the membrane protein nectin-4, which acts as a transporter carrying the virus through epithelial cells. Lenzen-Schulte also reports that the effect may explain why cancer cells, which often overexpress nectin-4, are vulnerable to measle and other viruses. This might pave a way to develop new oncolytic viruses.
Ernst-Ludwig Winnacker, the nestor of the German biotechnology industry, makes the case for green biotechnology in the weekly Die Zeit. Winnacker criticizes the concept of coexistence that tries to avoid a blending of genetically modified and conventionally bred plants by defining a minimum distance between cultivated areas. In Germany, a farmer cultivating GMOs is liable for every case of cross-breeding, a provision that effectively prohibits GMO cultivation as there is a zero threshold for “contamination”. Winnacker also criticizes the strategy of patenting genetically modified plants instead of protecting them with the traditional plant variety rights that allow for exemptions for the further use of GMOs by breeders and farmers. Green biotechnology, he writes, has – at least in Europe – become the scapegoat for everything that is wrong with modern agriculture, from monoculture to declining biodiversity to the death of bees, although Europe is almost free from GM plants. As 25 years of research into the risk of green biotechnology have not been able to reveal any real danger, Winnacker proposes to amend the German law on genetic engineering and to simply omit the measures restricting the cultivation of GMOs.
Diabetics may soon be able to measure blood sugar without pricking, reports Der Spiegel. A new technology developed by researchers of John’s Hopkins University enables measuring of blood sugar in tear fluid.
In Wirtschaftswoche, Matthias Hohensee introduces US-based 23andme company which offers genetic testing at a rate of $99 plus a flat fee of $9 per month for access to the data. The company, which was criticized for exaggerating the benefits of personal genetic testing, also changed its business model and is now offering its records comprising the data of 125,000 people for research purposes, e.g. to find out why certain hereditary diseases display incomplete penetrance in different carriers of the respective genes.
Theres Lüthi in Neue Zürcher Zeitung (NZZ) reports on clinical studies by Roche and Novartis in people suffering from Down’s or fragile X syndrome in an attempt to improve cognitive abilities.
Alyson Krueger in Forbes reports on a talk on synthetic biology given by Andrew Hessel of Singularity University during the Technonomy 2011 conference. Hessel describes synthetic biology as computer-assisted genetic design that goes from an idea to printing DNA to ultimately booting DNA and forecasts it will render the task of engineering life as straightforward as programming software, or creating a vaccine as simple as Tweeting.
Alex Knapp, also in Forbes, describes a “cyborg yeast” designed by researchers from the University of California at San Francisco and ETH Zurich, Switzerland. In the yeast, the expression of a certain gene can be switched on and off by different shades of red light. The technique may lead to advances in the production of proteins by yeast cultures.
The Economist reports on the first computational pathologist which can can distinguish between grades of breast-cancer cells to provide a more accurate prognosis than a human pathologist can manage.
And finally, scientists found a single gene which can make you appear kinder, reports Catherine de Lange in New Scientist. In experiments conducted at the University of Toronto, people with the so-called GG version of the oxytocin receptor gene were judged to be kinder than those with GA or AA versions. Those with GG variations used significantly more non-verbal empathetic gestures in their storytelling such as smiling and nodding which made them appear kinder.
Germany’s new Law on the Reorganization of the Pharmaceutical Market (AMNOG), which came into force January 1 this year, has substantially changed the rules for the introduction of new medicines on the German market. The akampioneer already has reported on the novel regulations and procedures – now it is time to look at the consequences AMNOG has had already.
Since the beginning of 2011, 18 dossiers for the required benefit assessment have been filed with the Federal Joint Committee G-BA, the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany. G-BA is then assessing the “additional patient-related benefit” of a novel drug, either itself or by assigning Germany’s Institute for Quality and Efficacy in Health Care (IQWiG). If G-BA identifies an additional benefit, the umbrella organization for the statutory health insurance funds and the pharmaceutical company negotiate the reimbursement price as a discount on the original selling price within six months. If negotiations fail to reach an agreement, an arbitration commission defines the reimbursement price using the European price level as a standard.
Most cases are still pending. In one of the 18 cases (the statin pitavastatin marketed by Merckle Recordati in Germany) , the manufacturer itself requested the drug to become reimbursed under the fixed price system. In two cases, marketing was halted in Germany by the manufacturer following a negative G-BA assessment: Boehringer Ingelheim and Eli Lilly decided not to market linagliptin, a DPP4 inhibitor for the treatment of type II diabetes; the companies think G-BA chose the wrong therapy for comparison and assessment of the additional benefit.
Novartis removed Rasilamlo from the market, effective September 1. The oral drug is a combination of aliskiren and amlodipine, which was approved in April this year for the treatment of high blood pressure patients not adequately controlled by either aliskiren or amlodipine alone. The company could not get to terms with G-BA on the data required for the assessment of the additional patient-related benefit.
The decision not to market a drug in Germany if the assessment is negative and the setting of a low price is imminent certainly reduces sales; on the other hand it prevents the setting of a lower price in other European countries that use Germany’s drug prices as reference.
The first completed assessment regards AstraZeneca’s platelet aggregation inhibitor ticagrelor, which was approved in December 2010 for the prevention of thrombotic events in patients with acute coronary syndrome or myocardial infarction with ST elevation, and is intended to be used in combination with acetyl salicylic acid (ASS). G-BA had assigned IQWiG with an assessment that deviated from the design of the studies used for approval and from the comparator therapy G-BA originally had agreed upon with the manufacturer. For approval, the drug had been compared to clopidogrel (plus ASS). IQWiG, however, defined subgroups and compared ticagrelor plus ASS with clopidogrel plus ASS in patients with unstable angina pectoris and myocardial infarction (with and without ST elevation) and prasugrel plus ASS as a comparator for patients with ST elevation, which had received a coronary bypass or a percutaneous coronary intervention (PCI) .
As a result, G-BA ruled that the drug has an additional benefit only in patients with myocardial infarction without ST elevation and in patients with unstable angina pectoris. In these cases, G-BA sees a moderate additional benefit. IQWiG had stated that the data provided by the manufacturer to support efficacy in patients with ST elevation did not sufficiently prove additional benefit in this subgroup.
While it certainly is a good idea to ask whether a novel drug not only meets regulatory requirements but also translates into patient benefit, the process of assessing this benefit and the degree of improvement as compared to existing therapies is a mess in Germany.
One important point is transparency. The crucial selection of the comparative therapy for the assessment takes place behind closed doors in G-BA’s pharmaceutical subcommittee. G-BA does not even disclose the subcommittee’s members – however, it is known that the members are picked from the National Association of Statutory Health Insurance Physicians and from the Statutory Healthcare System. The cheaper the comparative therapy chosen, the bigger is the hurdle to meet the cost/benefit ratio.
Second, as compared to the NICE procedure in the UK as an example, manufacturers are not involved in the process once it has started (except that they may be asked to submit more data), and if they are not happy with a decision the only possible procedural intervention is taking G-BA to court. Otherwise, they may wait for a year after which they can file an application for submitting novel data – which may be granted by G-BA or not.
Third, it is often very difficult to prove an additional benefit of an innovative medication immediately – except maybe for an antibiotic. Therapies for chronic diseases lead to measurable improvements often in the long or medium run only, and regulatory studies often are not large or long enough to meet the strict “evidence-based” criteria of IQWiG and G-BA. In addition, elderly patients often suffer from multiple diseases, making an assessment even more difficult.
Last not least, for the reference price system the devil is in the details. Will all European countries, including the poor economies of the former communist countries in Southeastern Europe, be included – or only the richer economies of the old European heartland?
All in all, the new regulations already have led to a slowing-down of novel drugs reaching the German market – a development that IQWiG’s new director Juergen Windeler in a recent interview declared as “expected”. He might as well have said “welcomed” as he added that of the about 60,000 drugs on the market in Germany, 95% were dispensable: “Experience shows that good medical care is possible with 2,000 to 3,000 drugs only.”