BioM: Mr. Dauer, now that the summer break is over, how would it be if we briefly reviewed the most recent events at 4SC and ventured a look into the future? I should like to start with an announcement that met with a response that was not quite so positive, namely the Phase II data of the 4SC drug “Vidofludimus” in rheumatoid arthritis.
Dauer:
We have strategically positioned 4SC so that the company’s fate is not dependent on a single drug candidate. With 5 substances in clinical development, 2 of which are drug candidates in several Phase II trials, 4SC has a broad and well-balanced development pipeline. This enables us to control the risks involved in developing the pharmaceuticals and to cope with setbacks much better.
And you are right. In a clinical Phase II trial involving patients with rheumatoid arthritis (RA), Vidofludimus did not meet the goal we set ourselves, namely the primary endpoint. A closer analysis shows, however, that Vidofludimus was definitely efficacious in this trial – for example, we reached several secondary endpoints that were of statistical relevance.
BioM: Does that mean that the drug experts are still optimistic, even thought the financial experts on the stock exchange had already begun to give the project the thumbs-down?
Dauer: Absolutely – and the reaction from the stock market is of course not always all that well founded and in my view it was also exaggerated in this case. Our negotiations with the pharmaceutical companies still look very promising, because, after all, with a major indication like RA next expensive development studies for Vidofludimus will anyway require the support of a partner. Our negotiating partners still think that Vidofludimus has great potential, especially if you consider that the RA indication is dominated by expensive antibody-based therapies that are often accompanied by strong side-effects – here, our orally administered, well-tolerated low-molecular compound Vidofludimus, which is also less costly to produce, is thought to be an attractive therapeutic option.
BioM: Vidofludimus is also being developed for other indications. What is the situation there?
Dauer:
Particular mention must be made of IBD, that is, forms of inflammatory bowel disease such as Crohn’s disease and ulcerative colitis. Here, we published very promising Phase II data with impressive patients’ response rates in autumn 2010. We are now negotiating the structure of the next trial with the regulatory authorities. In view of the great medical demand in the field of IBD – only think of the frequent and sometimes drastic side effects with standard therapy using corticosteroids – we are optimistic about the next development stages on the way to approval, which we intend to tackle promptly with the support of a powerful partner from the pharmaceutical industry. For me, Vidofludimus continues to be an extremely exciting substance that also has blockbuster potential when it comes to the various forms of chronic inflammatory bowel disease. Apart from this, Vidofludimus has a lot of potential looks promising as an immune modulator in further autoimmune diseases such as, for example, lupus.
BioM: The next far-advanced candidate is Resminostat, your HDAC inhibitor.
Dauer:
As with Vidofludimus, we also regard Resminostat as a “synthesis of the arts” with broad therapeutic usage options in several indications. Resminostat is a so-called “pan”-HDA inhibitor that can inhibit all of the many different classes of this group of enzymes that plays an important role in gene regulation. There are three development paths that we are pursuing:
First of all, the drug is used as a monotherapy, especially with Hodgin’s Lymphoma (HL), for which we published very good data at the beginning of September. In this “niche indication” – there are around 20,000 new cases of HL in Europe and the USA every year, of which 80 percent generally respond well to standard chemotherapy – we have now been able to demonstrate for the first time the anti-tumour efficacy of this molecule in a clinical trial and thus to validate Resminostat, which is also extremely well tolerated by the patients. The target group of our trial were patients who do not respond to standard therapies or had ceased to do so. As these patients have no further therapeutic option available, the medical demand is especially high here.
The second indication is heptocellular carcinoma (HCC) for which we have already been granted orphan drug status. You would think this would actually indicate a small patient population. Cancer of the liver, however, is a very big issue, especially in Asia, for example, in Japan and China. The medical demand here is also high. Today, HCC is the third most frequent cause of death worldwide, due to cancer. There is currently no second-line treatment option – In a current Phase II trial in combination with Nexavar, another targeted therapy, we were already able to announce good interim results in June for Resminostat in second-line treatment and we are not the only ones who are eagerly awaiting the final data (by the end of 2011).
The third indication we are tackling is colon cancer. Here Resminostat is tested in combination with a standard form of chemotherapy in patients with KRAS tumour mutations.
BioM: In view of the different indications in blood, liver and colon cancer, what is it exactly that makes Resminostat a “master molecule”?
Dauer:
Well, you used the word ‘master molecule’. But we do indeed see a very broad range of applications for Resminostat in view of its special, targeted mechanism of action as an HDAC inhibitor and its excellent tolerability, as regards its possible therapeutic uses and combinations, and the treated types of tumours and indications. HDAC plays a crucial role in epigenetics, and especially in the regulation of gene activity. In the case of tumours, this regulation has gone out of control. Resminostat modifies the genes’ expression patterns, causing the differentiation of tumour cells, thus promoting apoptosis, in other words, the programmed death of the cancer cell. What one can also observe in connection with HDAC is that, with certain tumour patients, certain genes are upregulated or downregulated. We are taking a very close look at how and with which patients the gene expression patterns are influenced by this drug.
BioM: Are you referring to genomic biomarkers, which are also becoming increasingly important when it comes to selecting patients?
Dauer:
Exactly. Biomarkers have become an integral part of our research and development work, be it to improve the accuracy of a drug or to be able to use a detailed profile when it comes to recruiting patients for clinical trials.
Another example of the targeted therapy approach we are pursuing for certain patient populations is the use of Resminostat in the treatment of colon cancer. Here, we are focusing on patients with KRAS tumour mutations. These patients, who account for around 40 percent of colorectal cancer patients, do not respond to the current second line treatment using EGF receptor antibodies such as Erbitux – and could therefore benefit most, should our new development prove successful. We do not expect any results from this Phase I/II trial before 2012.
BioM: It is (sometimes) not a great step from biomarker to diagnostic agent. Are you also pursuing similar developments?
Dauer:
Not ourselves. There are others who can do that better. But we are in contact with diagnostics companies, because the findings about the gene expression patterns using HDAC inhibition are an ideal interface to develop cooperations in this field. What we hope to obtain is a subset of predictive biomarkers that will help us in our development work –so we can offer the best possible therapeutic option through the best possible patient stratification.
BioM: Along with Resminostat, 4SC is developing a further HDAC inhibitor. Aren’t you simply competing against yourselves?
Dauer:
No. The 4SC-202 molecule you are referring to interacts specifically with only one particular subtype of the HDAC enzyme class, whereas Resminostat as a “pan” HDA inhibitor has a much broader scope. 4SC-202 exhibits a very strong cytostatic (anti-mitotic) effect, which is why we are deliberately developing this compound so that we can treat tumours that proliferate extremely rapidly. This makes it less a competitive product, but, if we are successful, a supplement with additional potential.
BioM: Talking about competition, HDAC inhibitors are also being developed elsewhere. How do you regard the position of Resminostat in this race?
Dauer:
HDAC is an attractive validated target – so of course there is competition! But on closer examination the developed drugs differ considerably, for example, with respect to the mechanism of action or as regards their pharmacokinetics, and we are optimally positioned with Resminostat. So far, all studies have shown that Resminostat is extremely safe and has a high level of tolerability. Its pharmacokinetic properties are also excellent: we are achieving very high plasma levels, in other words the patient receives a sufficient amount of the substance for it to be effective. Also, there are only a few others that are more advanced than we are. Resminostat is, for example, the first HDAC inhibitor in the HCC indication. The fact that we received orphan drug status for HCC shows that the regulatory authorities consider the mechanism of action to be very promising for this indication.
BioM: 4SC also has other projects in the pipeline. What is the situation there?
Dauer:
As already mentioned, 4SC has a clear strategy, and that it not to ride the famous “one-trick pony”. So we are deliberately developing a broad pipeline and have many more projects at the clinical and late preclinical stage. 4SC-203, our multi-target kinase inhibitor has completed a successful Phase I trial and we will soon decide about the tumour indication when it comes to its further development. 4SC-205 is another molecule with a very interesting new mechanism of action, which we are currently testing for the first time in patients with haematopoietic and solid tumours as part of a Phase I study. This Eg5 kinesin inhibitor blocks the cell division process, and hence the multiplication of tumour cells, by inhibiting a motor protein of the spindle apparatus. To put it simply, 4SC-205 is supposed to work in a way that is basically similar to the famous chemotherapeutic Taxol, but without the irreversible neurological damage caused by Taxol’s toxicity. And finally there is 4SC-207, a novel cellcycle blocker which we have evaluated in a preclinical study and which is on our clinical agenda for 2012.
BioM: Let’s conclude by returning to a topic mentioned at the beginning: 4SC will not be able to take these clinical projects to approval without partnerships. For Reminostat, you were able this year to announce a cooperation in Asia with Yakult Honsha, the market leader in the field of gastrointestinal cancer therapies in Japan. What are you going to do next in this respect?
Dauer:
As already mentioned, we are currently conducting negotiations with several big pharma and biotech companies about the worldwide marketing rights for Vidofludimus and about partnering for Resminostat in Europe and America. Basically speaking, the more and the better the results are that one can provide as a company about the efficacy and active principle of a substance, the better it is for these negotiations. This applies particularly to fields in which drugs are already on the market or fields in which there is a large body of knowledge about how these drugs work, for example, in the case of HDAC inhibitors. We have high expectations of the data on Resminostat as regards liver cancer, which we even expect to receive this year. In other cases where we are addressing completely new promising active principles with our agents, for example with 4SC-205, we regard a partnering deal as possible even before the clinical proof of concept.
BioM: Dr. Dauer, we like to thank you for this interview and wish 4SC all the best for the future.