NWBO DCVax-L Phase III Randomized Trial Models Significant Survival Improvements

Summary

• NWBO has reported that top line data for their sentinel long follow-up  phase III  (Glioblastoma multiforme) GBM brain tumor randomized trial will be completed by Mid to Late Sept 2020.
• This Binary event will have significant effects on the future Value of NWBO.
• The development of model Kaplan Meier overall and PFS survival curves showing a significant survival advantage for the Vaccine is discussed and reviewed with supporting references.
• The Primary investment thesis is that this phase III trial will return a statistically significant positive result causing an increase in the valuation for this stock. Current Stock valuations do not reflect a positive result for this phase III trial.

Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor that affects over 12000 people in the USA yearly. ¹ Treatment for GBM is primarily surgery followed by Radiation and chemotherapy postoperatively. The current standard of care for treatment is evidenced by a randomized trial published in the New England Journal of Medicine (NEJM) commonly known as the Stupp Trial ²

The Stupp Trial showed a modest 1.9 month improvement in median Progression Free Survival (PFS) with use of chemotherapy with Radiation therapy and that chemotherapy become a multi-billion dollar drug. Since the Stupp trial has been published there have been few advances that have moved the needle of survival in this devastating disease.

Researchers from UCLA developed a Dendritic Cell Vaccine specifically designed to attack the antigens presented by the GBM tumor and had very good outcomes in Phase 1 trials

NWBO is a development stage biotech company that for over 10 years has been painstakingly shepherding a large phase III randomized trial which reviews the potential efficacy and safety profile of this Dendritic cell Vaccine. Recently NWBO has indicated that the top line data will be completed in Sept 2020.

This Binary event will have very significant effects on the future Value of NWBO

Recent Kaplan-Meier (KM) Modeling shows that the likely outcome in Overall Survival and PFS for this trial likely will be a practice changing significant improvement for patients with this devastating disease.

The rationale for the model and the model assumptions are noted below:

Additional detailed information regarding this KM Model can be found in the following videos links which explain this model more definitively.

NWBO DCVax-L PFS Model

And

NWBO DCVax-L PFS MODEL NUMBER 2

MODEL ASSUMPTIONS and review

Hypothesis 1: The Control Patients in the DCVax-L GBM trial should relapse at a rate similar to what was shown in the IMUC trial because the IMUC trial and very similar entry requirements to the current NWBO DCVax-L Trail. The progression free survival (PFS) was reported at the 2014 American Society of Clinical Oncology (OTC:ASCO) meeting. The Overall Survival (OS) and PFS curves where published and the data points are known for these patients.

Hypothesis 2: Given that we know the number of PFS events in the total DCVax-L trial at the time of the first interim analysis was 66 December 2013 and that there where 248 PFS events on before 2/1/2017, as reported by NWBO PR news releases at those times, then one can model using statistical software, model the control arm PFS for the DCVaX-L trial to be the same as the corrected IMUC trial results and thus obtain an estimate of the probable number of events required for the control arm of the DCVax-L.

When one does this with a Kaplan Meier plot, one obtains the number of events required for the DCVax-L control group to be equivalent to the IMUC control group. 

Then one can deduce that the number of events in the experimental arm for the DCVax-L trial would be 248- 100 or 148 events in the experimental ARM.

Hypothesis 3: Using the derived 148 PFS events in the experimental arm, one can model the experimental arm to be the same as what was shown to the IMUC control arm trial results but, in this case only allow for just 148 events out of 220 total patients in the DCVax-L experimental arm.

When one does this with a Kaplan Meier plot, the data and curves are shown below. When one applies log-rank and Wilcoxon significance testing to the two curves one obtains a significant result of p<.0001 PROGRESSION FREE SURVIVAL MODEL

Green is the DCVax-L treated patients

A Similar analysis was completed on overall Survival (OS) for the treatment and experimental arms using the Blinded published data from the Translational Medicine article as noted:

Liau et al. J Transl Med (2018) 16:142 First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

RESEARCH First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

This article provided numerous data points used in development of the OS model:

The article further states  that "Long tail among ITT population with immune-based therapies, a key focus is on the tail of the survival curve [3]."

And

"Among the ITT patients with a surgery date ≥ 30 months prior to the data collection (n = 223), 30% (n = 67) have lived ≥ 30 months, and their KM-derived median overal survival (MOS) estimate is 46.5 months"

And

"Among the ITT patients with a surgery date ≥ 36 months prior to the data collection (n = 182), 24.2% (n = 44) have lived ≥ 36 months and their KM-derived median overal survival (MOS) estimate is 88.2 months."

Overall Survival DCVax-L Model     DCVax-L in Green;  Control in Red

Statistic	Observed value	Critical value	p-value	alpha
Log-rank	6.556	3.841	0.010	0.050
Wilcoxon	4.231	3.841	0.040	0.050
Tarone-Ware	5.615	3.841	0.018	0.050

For more detailed explanations, please review the video link which giving the model of the hypothesis for the non blended results and shows how this model is painstakingly created.

NWBO DCVaX-L Overall survival model unblinded

In Conclusion based on available data my best-educated hypothesis is that clearly, the DCVax-L trial is going to return a positive result on the primary end point (PFS) and secondary endpoints (OS).This result will be a practice changing result, especially when one sees the plateau in the treatment curve. 

Just to put this into perspective the Stupp GMB trial PFS only increased 2 months by the addition of temazolamide (TMZ) (5 to 6.9 months). Yet this became almost immediately, the new gold standard of care in this disease and TMZ almost immediately became a blockbuster multi-billion dollar drug.

DCVaX-L increase in the operable patients may be even more than this and with has none of the chemotherapy side effects. This will quickly be the new standard of care in this disease. With a positive result, patients and providers will demand this therapy to improve the survival odds.

With a positive phase III Trial result, the NWBO valuation will likely increase significantly consistent with the primary thesis of this article.

Once this platform for dendridic cell vaccine is validated by this phase 3 trial and more exciting to me, is the potential use of DC Direct Vaccine which can be used in any inoperable tumor and has a very wide applicability to many diverse cancers.

References

1.Gliobastoma; De Vleeschouwer S, editor. Brisbane (AU): Codon Publications; 2017 Sep 27.

2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96

3.Liau et al. J Transl Med (2018) 16:142 First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma