Expert Financial Analysis and Reporting

Key Points:

• On December 21, 2023, NWBO announced that it had submitted its MAA seeking regulatory approval for DCVax-L in the UK.
• The Company requested that MHRA review DCVax-L using the accelerated pathway and, in this report, I go over the reasons why I think the MHRA will do so. (The section in this report titled “Under the UK’s Early Access to Medicines Program, MHRA Review Could Be Swift” explains my thinking in detail.)
• Under the accelerated pathway, the MHRA tries to review the application in 150 business days or less. This indicates a decision on approval could come by mid-June, 2024. However, this is only a goal and not a firm commitment and the MHRA is not tied to this guidance. I think that approval will more likely come in 3Q, 2024. This is lightning speed for a regulatory agency.
• I believe that the MHRA will not make any public statement on whether DCVax-L is being reviewed under the accelerated pathway nor will it make any comments during the review period. This is not how regulatory agencies work.
• My conclusion about accelerated approval for DCVax-L is supported by the agency’s actions with the rapid approval of Pfizer’s COVID vaccine Comirnaty. Initial data was submitted to MHRA on October 1, 2020 and conditional approval was granted on December 2, 2020. Pfizer only issued one press release on the review process and this was on December 2, 2020, the day on which Comirnaty was approved.
• The next we will hear from MHRA, in my judgment, is that DCVax-L has been approved or not. I rate the probability of approval at 95%.

 

Acronyms Used in This Report

This glossary of acronyms may help in reading this report.

CDMO   Contract Development and Manufacturing Organization companies provide biopharma companies with comprehensive services ranging from drug development through manufacture. Northwest uses the UK firm Advent BioServices as a CDMO.

EMA  The European Medicines Agency (EMA) is the European Union equivalent to the FDA.

GBM   Glioblastoma Multiforme is the most aggressive and deadly type of brain cancer, ndGBM is newly diagnosed GBM and rGBM is recurrent. These are the two indications initially being sought by Northwest Biotherapeutics for DCVax-L

GMP   Good Manufacturing Practice is a system required by regulatory agencies for ensuring that drugs are consistently manufactured according to carefully defined quality standards. Guidelines address issues such as process validation, quality assurance assays, record keeping, personnel qualifications, sanitation, cleanliness, equipment verification and others.

MAA  Marketing Authorization Application is the document that must be submitted to the MHRA (and other European regulatory agencies)  by companies seeking approval for a drug. The MIA is an integral part of this submission. Approval of the MAA allows commercialization. This is the counterpart to the BLA in the US.

MHRA    Medicines and Healthcare products Regulatory Agency is the United Kingdom regulatory counterpart to FDA. The two agencies have a close, collegial working relationship. Approval of DCVax-L by MHRA would carry great weight in the FDA’s decision making.

MIA   Manufacturer's Importation Authorization is required by the MHRA before a company  can manufacture, import or export drugs. To qualify, a manufacturer needs to demonstrate to MHRA that it complies with good manufacturing practices (GMP) and can pass regular GMP inspections of its manufacturing site.

PIP Pediatric Investigation Plan  Under applicable UK law, a new medicine that is developed for adult patients must also be tested for potential application to pediatric patients before it can gain approval in the adult population. Approval in the adult population can be granted before such trials are started at the discretion of the MHRA.

SOC   Standard of Care is the currently accepted treatment regimen for a disease. In the case of GBM, this is surgical resection followed by radiation and then the chemotherapy drug temozolomide following.

SAP  Statistical Analysis Plan describes how the quantitative or qualitative data collected in a trial will be statistically handled.

Catalyst For This Report  

Northwest Biotherapeutics issued a press release on December 21, 2023 announcing that it had filed its MAA seeking approval in the UK for DCVax-L in adult patients with either newly diagnosed or recurrent glioblastoma. The submission of the MAA is a critical step. Approval would validate that NWBO’s dendritic cell vaccine technology is a major advance in the treatment of not only GBM but potentially all solid tumors. This could propel NWBO to being one of the most exciting stories in biotechnology over coming years and decades, possibly the most exciting.

Investment Overview

In this report, I don’t discuss a specific price target. It is intuitively obvious that MHRA approval of DCVax-L for GBM would have an extremely positive impact on the stock, possibly increasing the stock price to multiples of the current price. And yet, this is only the beginning of the investment story. The mode of action for dendritic cell vaccines of which DCVax-L is the first, holds the promise for meaningful effectiveness in all resectable solid tumors. Hence the potential pipeline for DCVax-L beyond GBM is staggering. Management has indicated that NWBO plans to pursue clinical development of DCVax-L or other types of dendritic cell vaccines in potentially all types of resectable solid tumors-ovarian, lung prostate, breast, et. al. This is an immense addressable market.

New indications will be addressed not only by dendritic cell vaccines as a single agent as is common in cancer therapy, but also in combination with other oncology drugs. As one very promising example of the potential for combinations, an unpublished phase 2 trial has been performed in 24 GBM patients at UCLA in which DCVax-L was combined with Merck’s checkpoint inhibitor Keytruda and polycytidylic acid (poly IC). Kaplan Meiers statistical analysis projected that 50% of patients would survive eight years. This is remarkable when viewed against a five year survival for SOC of 5%. The phase 3 trial of DCVax-L  plus SOC showed five year survival of 13% which itself was remarkable as compared to SOC. It seems probable that Merck will be looking to do more extensive combination trials with Keytruda involving DCVax-L and poly IC.

These promising/ spectacular results could also induce some of the other manufacturers of check point inhibitors to undertake combination trials with DCVax-L. Regeneron, Roche and Bristol-Myers Squibb all come to mind but there are others. Combinations with many other types of oncology drugs are also probable. Let me re-emphasize that the mechanism of action of dendritic cell vaccines means that they potentially could be effective in all resectable solid tumors. So, there are a vast number of potential cancer targets and combinations with other drugs to be pursued.

UK Approval Would Transform Northwest Biotherapeutics into A Premier Commercial Stage Biotech

Approval in the UK is a critical starting point for the global clinical development and commercialization of DCVax-L and future products based on the dendritic cell vaccine technology. A validation accorded by UK regulatory approval would have very positive consequences.

• The EMA and FDA both have great respect for the MHRA that should lead to a positive perspective and would likely expedite their regulatory reviews. Moreover, there is an urgent need for improved therapy in GBM as no new drug has been shown to meaningfully extend survival in ndGBM since temozolomide in 2005 and for rGBM since the mid-1990s with the Gliadel wafer. UK approval would likely result in considerable pressure on EMA and FDA from advocacy groups for expedited review.
• Canada has a very close working relationship with the UK which could lead to approval not long after the UK.
• The commercial approval of the Sawston GMP cell manufacturing facility affords the capability of GBM patients anywhere in the world to send their resected tumor tissue and autologous cells to Sawston to have their personalized vaccine manufactured and then shipped back. Administration of the vaccine is a simple intradermal injection that can be administered in an out-patient setting. So even before approval in a given country, patients anywhere in the world potentially would be able to access DCVax-L on a compassionate use basis.
• NWBO disclosed in its recent 10-Q that it was in discussions for collaborations for clinical trials in which DCVax-L would be combined with other therapies. UK approval would greatly accelerate these discussions.
• The wolfpack’s criminal conspiracy to manipulate the stock price of NWBO with a purported goal of driving NWBO into bankruptcy would be thwarted.
• Numerous ways to access capital on favorable terms through collaborations and non-dilutive types of financings would be opened up.
• This would likely engender widespread investor enthusiasm and extensive Wall Street analyst coverage.

History will look back at Linda Powers’ decision to focus the limited resources of NWBO to first gain regulatory approval in the UK as a brilliant decision.

Critical Components of the MAA

The MAA filing comprises a staggering amount of information and there are many requirements to satisfy. However, I believe that the three most critical requirements that NWBO must meet in order for DCVax-L to obtain MHRA registration have been met. This is what gives me such great confidence that the MHRA will move quickly to approve DCVax-L. These are:

• Conducting a clinical trial that demonstrates efficacy as defined in a statistical analysis plan (SAP) approved by the MHRA. This box is checked as ten days after the SAP was filed, the MHRA published on its website that it had accepted the SAP. This means that the MHRA review will be based on evaluating the primary endpoint of mOS in ndGBM and the secondary endpoint of mOS in rGBM using matched contemporaneous external controls (independently selected by outside experts). Phase 3 results as reported in a peer reviewed article in JAMA Oncology showed that these endpoints were reached with extremely impressive p values. The p-value for mOS in ndGBM was <0.002 and the p-value in rGBM was <0.001.
• Approval from MHRA for commercial manufacturing of DCVax-L at the Sawston facility was obtained on March 20, 2023 following a three year process of preparations. This is a prerequisite for filing an MAA. Manufacturing issues pose a major challenge for emerging biotechnology companies and very frequently can be the cause of significant delays in approval. One year ago, I was more worried about a problem with manufacturing arising that could delay approval than I was with whether the MHRA would view favorably the clinical trial data. Not now.
• MHRA approval of clinical trial plans for pediatric trials in GBM was issued on August 16, 2022. This is also a prerequisite for filing an MAA. The PIP uses the same criteria as that for the adult GBM trials. The primary endpoint is mOS in ndGBM and the secondary endpoint is mOS in rGBM using matched contemporaneous external controls.

Under the UK’s Early Access to Medicines Program, MHRA Review Could Be Swift

The submission of the MAA was a material event for Northwest that under securities laws required public disclosure. This means that in order to issue the press release, the Company had to receive confirmation from the MHRA that the MAA had been received. Northwest also requested that DCVax-L be reviewed under the MHRA’s rapid 150-day review pathway, which the agency has established for new, breakthrough medicines that address serious unmet medical needs.

I do not expect  MHRA or NWBO to make any public statements about the pathway to a final decision or the details of the MAA review process now underway. Giving updates is just not how regulatory review works. The review period will involve many broad ranging interrogations and discussions between the MHRA, NWBO and the company’s various contractors and consultants. The very nature of the process involves highly confidential material of the agency, NWBO and myriad consultants, vendors, manufacturers and trial sites. All exchanges will be highly confidential. In my opinion, the next news we will hear from the Company and the MHRA is the final outcome of the whole process which will be a decision to approve DCVax-L or refuse to approve it. As previously stated, I rate the probability of approval as 95%.

I believe that MHRA will review DCVax-L under the rapid 150-day review pathway. Let me start with some background. In April 2014, the MHRA launched a new initiative called the Early Access to Medicines Program. The intent was to offer severely ill patients with life-threatening and seriously debilitating conditions the lifeline of providing access to ground-breaking new medicines much earlier than they would be the case with traditional review procedures.

Following an assessment of early clinical data, MHRA can designate a new drug as a Promising Innovative Medicine (PIM). This signals to a company that its development plan is on the right track and that its product could be a candidate for the Early Access to Medicines Scheme, when further development work has been conducted. This early boost to a drug’s potential is expected to be beneficial to companies, especially small and medium-sized enterprises, who can struggle to attract capital from investors during drug development. This is a key component of the strategy to make the UK a major center of biotech innovation by expediting approval of breakthrough drugs. It is extremely impressive that DCVax-L was the first drug out of all of biopharma to be awarded the (PIM) designation.

The MHRA will not make a public statement as to whether DCVax-L will be reviewed under the rapid 150 day pathway. However, there are several strong indications that it will use this pathway:

• The designation of DCVax-L as a Promising Innovative Medicine is obviously critical. Because this was the first such drug to be so designated, I would expect that MHRA has been closely following and is up to date on its clinical development.
• The SAP for the phase 3 trial stated that the primary end point was mOS in ndGBM, the secondary endpoint was mOS in rGBM and used contemporaneous external controls. Only ten days after submitting the SAP, MHRA announced on its website, that it was accepted. This indicates that the MHRA is comfortable with the design of the trial and its SAP.
• The MHRA approved the Sawston plant for commercial production of DCVax-L which is a prerequisite for product approval. This involved extensive interaction with the agency. Very importantly, this was only the third facility in the UK approved for commercial cell therapy manufacturing.
• The MHRA granted a license for the import and export of living cells and tissue for Sawston. Tumor tissue and autologous cells necessary for the manufacturing of DCVax-L can be imported from anywhere in the world, processed into the final product and exported back to the point of origin. This means that Sawston can be used to provide product for worldwide commercialization.
• Before an MAA can be approved for use in adults, a company must submit and receive approval for a plan for pediatric studies. NWBO submitted its proposed PIP to the MHRA in February 2022 and received approval on August 16, 2022. This prompt response is encouraging.
• A compassionate use or Specials program in the UK has been led by Dr. Keyoumers Ashkan, the lead European investigator for the phase 3 trial of DCVax-L. He is a top neuro-surgeon at King's College Hospital, the premier teaching hospital in the UK and Dr. Ashkan is one of the most respected neurosurgeons in the UK. This compassionate use program conducted at Kings College affords important data on real life experience. Based on his clinical experience, Dr. Ashkan believes that DCVax-L is a major therapeutic advance in the treatment of glioblastoma and should become part of standard of care. Such a strong endorsement from such a highly respected physician with extensive hands on experience could carry weight with MHRA. It seems highly probable that MHRA has closely followed this Specials program.
• The MHRA has shown that it can move swiftly to approve drugs under the Early Access scheme. The Pfizer covid vaccine was approved on December 1, 2020. This was 60 days after the first efficacy data was submitted to MHRA.

Brief Review of the  Extremely Positive Phase 3 Trial Results for DCVax-L

I previously commented on the results of the phase 3 trial of DCVax-L, but I will briefly repeat and then elaborate on the results. The primary endpoint specified in the SAP was mOS in ndGBM that was achieved with p<0.002; the secondary endpoint under the SAP was mOS in rGBM that was achieved with a p<0.001.

Perhaps more important, there was a powerful survival tail in ndGBM which showed 13.0% of patients alive at five years versus 5.7% for SOC. This is every bit as impressive as survival tails for the checkpoint inhibitors in recurrent non-small cell lung cancer and recurrent melanoma, aggressive cancers which are roughly equivalent to glioblastoma in terms of expected patient survival. Note that it was the demonstration of the survival tail that was key to Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo becoming multi-billion dollar drugs.

The survival tail for DCVax-L in rGBM showed that at 30 months after tumor recurrence, 11.1% of GBM patients were alive versus 5.1% in the control arm. No drug has  demonstrated a survival benefit in rGBM since the Gliadel wafer which was developed in the mid-1990s.

Very importantly, DCVax-L has an extremely favorable side effect profile as almost all side effects are minor. Virtually all other cancer therapies have dangerous, life threatening side effects. This enormously increases the benefit to risk ratio for DCVax-L in both an absolute and relative sense. It is also dosed with simple intradermal injections which can be administered in an outpatient setting, i.e. a physician’s office. Many other oncology drugs require lengthy intravenous infusions which are not always available in an outpatient setting.

Having read this, you may ask why I don’t assign 100% probability of approval? Well, nothing in life carries 100% certainty.

More Detail on  the Pediatric Investigation Plan (PIP)

Under applicable UK law, a new medicine that is developed for adult patients must also be tested for potential application to pediatric patients before it can gain approval in the adult population. NWBO was required to develop an overall plan to evaluate the safety and efficacy in pediatric patients. The PIP had to include all aspects required for approval, such as the patient population, eligibility criteria, stage of disease, treatment regimen, trial design and endpoints.

NWBO announced on August 16, 2022 received approval from the MHRA for the PIP This was based on two proposed clinical trials: one for ndGBM patients and one for rGBM patients. In each of the two pediatric trials, 24 patients will be treated with DCVax-L on the same treatment schedule as in the Company’s Phase III trial in adult GBM patients. As in the adult clinical trials, the primary endpoint for each trial will be overall survival, determined by comparing the survival of DCVax-L treated patients to matched contemporaneous external controls. The matched external controls will be identified using the same methodology as was used to pre-specify the matched external controls in the Statistical Analysis Plan for the Company’s Phase III trial in adult patients.

The final regulatory approval of the PIP must be obtained before a sponsor may submit an MAA for approval to commercialize a new medicine for adult patients. The approval may include a deferral allowing the pediatric clinical trials to actually be carried out after the MAA has been submitted, but the PIP approval itself must have been received before an MAA can be filed and go through compliance check.

Ordinarily, a PIP must go through a series of stages of regulatory review and comment to reach a final approval, a process that can typically take more than a year. In the case of NWBO, the company worked with expert consultants for months to develop a PIP which was submitted to the MHRA in February 2022. Approval was granted six months later on August 16, 2022. The speedy approval is encouraging and hopefully presages the speed with which MHRA will review the MAA.

The Critical Importance of Approval for Commercial Manufacturing of DCVax-L at Sawston UK GMP Facility

NWBO announced on March 20, 2023 that Advent BioServices (its UK CDMO), had been approved for an MIA license issued by MHRA for commercial manufacturing of DCVax-L and other cell therapy products at the GMP facility in Sawston, U.K. This license was the culmination of more than three years work, including development of the facility, the teams of specialized personnel, the Standard Operating Procedures (SOPs) and systems, well over 1,650 regulatory documents, and a successful operating history under the initial manufacturing licenses previously obtained to produce cell therapies in the Sawston facility for clinical trials and compassionate use. All of this work was carried out by Advent BioServices under contract with NWBO.

This MIA is one of the first licenses for commercial manufacturing of cell therapy products in the U.K. To the best of NWBO’s knowledge, there are only two other such licenses, one of which was just granted. Under this commercial manufacturing license, cell therapy products manufactured in the Sawston facility may be exported globally. Products (autologous cells) may also be imported into the U.K. for production or release of cell therapy products under the facility’s licenses. This allows GBM patients anywhere in the world to send their resected tumor tissue to Sawston to have their personalized vaccine manufactured and then shipped back. So even before approval in a given country, patients with adequate financial resources might be able to access DCVax-L on a compassionate use basis.

Why Dendritic Cell Vaccines Like DCVax-L Promise to be A Major Advance in Solid Cancer Therapy

The company’s press release of December 21, 2023 eloquently explains the reasoning that leads me to conclude that dendritic cell vaccines represent a novel, paradigm shifting approach to treating in not just GBM but all resectable solid tumors. I quote from the press release:

“One of the key factors making GBM so difficult to treat is that it is an extremely heterogeneous tumor. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure in GBM (Sottoriva, PNAS, 2013). Another key challenge is that as GBM develops, it induces an immunosuppressive microenvironment which compounds the difficulty of mounting an effective immune response against the tumor - especially within the central nervous system, which is an immune privileged space behind the blood brain barrier.

DCVax-L is designed to address both of these key challenges. As the Company previously reported, proteomic studies have demonstrated that a single tumor lysate sample contained tens of thousands of different peptides and, out of this pool, the dendritic cells selected, processed and presented over 600 different peptides (tumor targets) to T cells. T cell studies (TCR sequencing and T cell clonal expansion assays) analyzing the breadth and strength of T cell response following DCVax-L treatment have found extensive responses, including clonal expansion of up to 800 T cell clones at month 4 and up to 1200 T cell clones at month 8 in the samples studied. Each T cell clone focuses on a particular and distinct target. In individuals not being treated with the vaccine, only 2 – 20 new T cells clones are seen between month 4 and month 8.

The results of these proteomic, T cell and other studies provide support for what the Company believes to be the mechanism of action of DCVax-L: i.e., mobilizing a broad spectrum and strong de novo T cell response that addresses the extensive heterogeneity of GBM and overcomes the immunosuppressive microenvironment around the tumor.

The Company believes that this mechanism of action will be applicable for most types of solid tumors. Solid tumors comprise approximately 90% of all cancers, and a key difficulty that other treatment approaches have encountered with solid tumors is their heterogeneity.

The Company has already had positive results with DCVax-L in some compassionate use cases with other diverse solid tumors. The Company looks forward to building on its experience with DCVax-L in GBM and the compassionate use cases to address a wide range of other operable solid tumors.

The Company also had positive results in its Phase 1 trial of DCVax-Direct, in which more than a dozen diverse types of inoperable solid tumors were treated. DCVax-Direct involves essentially the same mechanism of action as DCVax-L, except that the tumor target proteins are taken up by the dendritic cells in situ in the tumor following intra-tumoral injection, rather than from tumor lysate from a surgically resected tumor tissue sample. The Company looks forward to resuming its clinical development of DCVax-Direct for a wide range of inoperable solid tumors.” (Note that the underlining for emphasis is mine.)

Epilogue

It has been a very long journey since the trial of DCVax-L began in 2007. This is an extraordinary story and I believe that it could well be the basis of a fascinating book and subsequent movie. Management has faced incredible challenges that have required courage, resolve and brilliant decision making that has gotten DCVax-L to the brink of approval in the UK. To casual or even seasoned investors, sixteen years seems an eternity although not unprecedented for a paradigm changing drug like DCVax-L. Consider CAR-T (another cell based therapy) which has revolutionized the treatment of hematological tumors. The first treatment of humans with CAR-T began in the mid-90s. The first trial in hematological cancers was conducted by the famous Carl June in 2012 and approval of the first CAR-T drug Kymriah, occurred in August 2017, which was 22 years after the first treatment.

The profound hurdles involved in the clinical development of DCVax-L were tragically exacerbated by short selling and other forms of attack that have been ongoing for over a decade. Unfortunately, this type of attack by incredibly greedy, manipulative short sellers on small companies (especially biotechs) is all too common. Short sellers have exacted a huge, tragic and outrageous financial impact on NWBO and shareholders. At least ten years ago, they began an attack on NWBO in which some of the participants openly stated that their goal was to bankrupt NWBO. I believe that this stock manipulation by a group of market makers and hedge funds using spoofing and other methods such as illegal naked shorting has been coincident with vicious social media fomenting. One short seller bragged that he and his co-short sellers would make the company and its management so toxic that no one would go near it. This has starved the company of cash and forced it to finance on highly unfavorable terms leading to significant share dilution. The filing of the MAA is a major step in eliminating manipulation of the stock by this “Wall Street manipulative short selling cancer” that plagues our financial markets.

In November of 2022, Northwest filed a suit alleging that Citadel and six other market makers conspired though spoofing to manipulate the price of NWBO over a multiple year period. Citadel has filed a motion to dismiss this suit and the Magistrate Judge is in the late stages of considering this. I believe that it will be denied and that NWBO’s legal counsel will be allowed to go forward with discovery. If so, Citadel and the six other accused market makers will be open to depositions of key personnel and subpoenas of trading records. This, in my opinion, will provide a clear roadmap of what I believe to be one of the largest criminal enterprises on earth. It is highly possible that some or all of these market makers will want to quickly settle. This will be the subject of a report on which I am now working.

 

 

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