Expert Financial Analysis and Reporting

Overview

Northwest Biotherapeutics stock was on fire yesterday as the price increased 35% to $1.12. The strength appears to be  attributable to two posts on the investor website iHub.

Thoughts on First Post

The first post was as follows:

“In the EU Clinical Trial register, it shows that the primary endpoint for the DCVax-L trial is Overall Survival (OS), not PFS (see Section E.2.1 and E.2.2). Also, the clinical trial register says that OS primary endpoint will be evaluated in October 2020 (see Section E.5.1.1). In Section E.5.2, it says that the "second secondary" endpoint is PFS. It also says that this secondary endpoint also will be evaluated in October 2020.”

Let me put this in perspective. The original primary endpoint of the DCVax-L phase 3 trial when it was begun over 12 years ago was PFS. This was in 2008 before the emergence of immunotherapies which effectively began in 2011 with the approval of the checkpoint inhibitor Yervoy. In 2008, clinical development was focused on chemotherapy and monoclonal antibody targeted therapies. For those products, PFS is a highly important endpoint as they primarily work by shrinking the tumor mass. This is much less the case with immunotherapies. It is quite common for medical imaging to show what appears to be an enlargement of the tumor after immunotherapy. However, it can then be the case that what appears to be a growth of the tumor is actually inflammation due to the immune system’s attack on the cancer or scar tissue from killed cells; this is called pseudoprogression. Hence, with immunotherapies it can be the case that imaging suggests that the tumor has progressed only to later find that there has been a meaningful therapeutic response.

Some have felt that there was a very real risk that pseudoprogression could be misinterpreted as actual progression. If so, the DCVax-L trial might fail on its primary endpoint of progression free survival and would be rejected by regulators. This risk is now removed in the EU as overall survival is now the primary endpoint .

Thoughts on Second Post

The second post was as follows:

“I just got off the phone with the clinical trial regulation department EMA. She confirmed that NO changes to clinicaltrialsregister.eu can be made directly by the sponsor. She told me that indeed only approved changes such as endpoints are submitted to the clinicaltrialsregister.eu IF the national health organizations in the specific countries have allowed and approved such. In the case of NWBO she confirmed that this has been recently done so. Also, she confirmed that in the case of NWBO this has been done so by the NHS in the UK and PIE in Germany.”

The obvious read is that NWBO submitted its Statistical Analysis Plan to the NHS and PIE and sought to have mOS become the primary endpoint. The agencies apparently agreed with the plan and they accepted mOS as the primary endpoint for the trial. The post stresses that this change to mOS as the primary endpoint was an action that only the regulatory agencies could make. NWBO could only suggest this change.

Further Investment Thinking

Northwest Biotherapeutics is in a self-imposed quiet period as the top line data from the phase 3 trial is imminent. They would offer no comment on these posts.

I must admit that I have long thought it was possible that NWBO could miss the primary endpoint of Progression Free Survival (PFS) because of pseudoprogression while achieving the endpoint of  Overall Survival (OS). However,  I frankly never was that concerned. I thought that if DCVax-L was successful on OS even if it were the secondary endpoint that the regulatory agencies would focus on the much more important survival endpoint and approve the product. My thinking was apparently not shared by a good number of investors who saw this latest news as a de-risking of the approval process and this seems to have been the catalyst for yesterday’s stock move. I must point out that this latest news carries no information as to whether the trial will be successful.

These posts don’t offer any insight into what the FDA might do. However, it is very difficult for me to believe that they would not agree with regulatory agencies in Europe on the appropriateness of using mOS as an endpoint. However, it is not impossible.

This news confirms that the European regulators are very much aware of DCVax-L and this is not surprising. The lead investigator of the European segment of the trial is Dr. Keyoumers Ashkan. He is the clinical lead for neuro-oncology at King's College Hospital in the UK and heads its Neuroscience Clinical Trial Unit.  Dr. Ashkan is one of the most respected neurosurgeons in the UK and Kings College is the premier teaching hospital in the UK. For more on Dr. Ashkan click on this link.  Dr. Ashkans is well known and his opinion carries much weight with English regulators. As the just cited link shows, he is very hopeful that DCVax-L could be a major advance in newly diagnosed GBM (ndGBM). There has been no new drug approval in newly diagnosed ndGBM since 2005 and it is one of the most aggressive cancers as median overall survival is about 17 to 18 months after surgery. New therapies are urgently needed

Dr. Ashkans has been treating patients in the UK on a compassionate use basis for some time. I am aware of two Americans who had the money to travel to the UK and pay out of pocket for DCVax-L treatment of their glioblastomas. (Anecdotal reports for both patients were positive.) I have no direct information on how many patients have been treated with compassionate use in the UK but it could be 2 or more per month for some time. Sorry to be so vague, but there is no public information on this that I am aware of. There are two important takeaways from this. The first is that regulators in the UK may be getting a glimpse of results from treating ndGBM patients on a compassionate use basis. The second is that they are comfortable that the manufacturing process at Northwest’s  Sawston, U.K manufacturing facility can provide reliable drugs to patients in the compassionate use program. If this is the case, at least in the UK and probably Europe, NWBO might be able to immediately supply GMP product following approval.

Why is this a big deal? Well we just saw why with Mesoblast’s cell based therapy Ryoncil. An Advisory Committee in the US recommended approval in pediatric graft versus host disease by a 9 to 1 vote. One month later the FDA issued a Complete Response Letter and did not approve the product over concerns about quality control in the manufacturing process. This is the result of the FDA not having much experience with cell based therapy manufacturing. Like Ryoncil, DCVax-L is a cell based therapy.  I am hypothesizing that the allowance of the compassionate use treatment in the UK indicates that NWBO has established manufacturing processes that are GMP compliant and reproducible. If so, Sawston could immediately supply product for Europe and presumably for the US. If this hypothesis is correct, it could mean a further de-risking of the approval process which is more important than the acceptance of the change to mOS as the primary endpoint.