Northwest Bio: Data Is Done, Just Wait For Approval (OTCMKTS:NWBO)

Last month, I was complaining about Northwest Bio (OTCQB:NWBO) not releasing data in a proper manner, which made it a confusing investment and a Hold for me. The company now is finally out with the topline data, published on November 17 on the peer-reviewed and well-regarded JAMA Oncology – here. The stock is up 70% and counting, one patient survived 8 years following DCVax-L treatment, a British patient survived 7 years, everything looks good, and all’s well with the world.

However, there’s talk about how the peer-reviewed article missed a few key points – the FDA’s partial clinical hold, the crossover design and the change in the endpoint – and how these things will make life difficult for NWBO. Well, they may or may not do so, but what these arguments miss is that I have never come across a peer-reviewed original investigation report that discusses anything but data and results. These other things are in the realm of the retail investing public – bears and bulls – and it is not the job of JAMA to figure that out. They only discuss data.

And the data was outstanding. Another thing I have hardly ever seen is a JAMA article with 67 named authors. Ms. Linda Powers has given this publication all she had, knowing full well that if there’s something that should shut the critics up for good, it would be from a publication like this with named authors who read like the who’s who in glioblastoma expertise. [see appendix below for list of authors/affiliations.]

I wanted to put that out in order to show you that the scientific community seems to have given this all they could and have come together to support Dr Linda Liau’s discovery of DCVax-L.

Now let’s review the data. Here it is, short and sweet and to the point:

A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (MOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).

The active treatment here was DCVax-L plus standard of care temozolomide, which was approved nearly two decades ago. External control nGBM (newly diagnosed GBM) patients received temozolomide and placebo; while rGBM patients received “approved GBM therapies,” where there is no SOC. Results were statistically significant. I note that almost every endpoint measured except the methylated MGMT one achieved statistical significance. As the authors also note, “only 1 phase 3 trial in nGBM and no phase 3 trials in rGBM have demonstrated a survival benefit” since 2005. This successful phase 3 trial was with TTFields, a promising new therapeutic modality, plus temo. While PFS was the primary endpoint, OS was a secondary endpoint and the data was as follows:

Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.

Note that for the nGBM population, DCVax-L also demonstrated 19.3 months of OS versus 20.9 months for the TTFields trial, however placebo had a 0.5 months higher survival in DCVax-L; of course, these cross trial comparisons do not really work. What should be noted is that both new therapies worked in nGBM; and DCVax-L also worked in rGBM patients, where nothing else works.

In the US, more than 13,000 people will be diagnosed with GBM in 2022 according to the National Brain Tumor Society. In the EU, there should be an equal number of patients; the UK alone has 2500 patients. Indeed, the EU number is actually quite a bit higher, at 22000 patients, according to this source. GBM occurs more in the developed countries than in the rest of the world; while this could be caused by underreporting, as one understands, the market is truly in the developed countries. There are some 1771 Japanese patients. From China, I had PBT (primary brain tumor) mortality data, which stood at 21,215. Assuming a 70% mortality and a 50% GBM among these PBT patients, I get a figure of 15,000 Chinese patients with GBM; which sounds a bit low given the population, and may or may not be caused by underreporting. Thus, there could be as many as 50,000-60,000 patients in the developed/relatively developed world for GBM. This is the target population for DCVax-L. Median treatment cost for GBM patients could well cross $100,000, and I wouldn’t be surprised if it goes beyond $200,000 per year. A treatment that extends OS significantly can be priced in the ballpark range – probably higher given how some very well-known people have succumbed to GBM. What that means is that a lot of people who could afford treatment did not survive due to a lack of it, so that could inform pricing. If we put it – quite randomly – at $200,000, then the total addressable market in the developed world comes to $12bn. TTFields treatment was approved for GBM patients by the FDA.

Coming back to the JAMA-Onc report, here’s something interesting – and to me, definitive- that it says about the crossover design:

Many trials, especially for incurable diseases, incorporate a crossover design for feasibility and/or ethical reasons. A crossover was considered necessary when our study began in 2007 to make patient enrollment and retention feasible when novel immunotherapies were not yet generally viewed as promising for cancer. The crossover was also important to justify the placebo group for patients undergoing a leukapheresis—an invasive procedure necessary for blinding and for manufacturing vaccine but offering no benefit to patients in the placebo group if they could not receive their autologous vaccine.

I think we can put that issue to rest.

Another issue that had vexed investors was pseudo-progression. The company explained why a change from a PFS endpoint to OS was necessary in order to avoid pseudo-progression:

The PFS end point became infeasible for this trial due to the challenges now well recognized in trying to distinguish true progression from pseudo-progression (including vaccine-induced immune cell infiltration).¹³ There were 494 imaging time points when possible progression was observed by the independent radiologists, and 256 of these (>50%) required adjudication due to discordant interpretations. Based on these assessments, the median PFS was 6.2 (95% CI, 5.7-7.4) months for patients receiving DCVax-L and 7.6 (95% CI, 5.6-10.9) months for the placebo group. This difference was not statistically significant (P = .47).

I have no particular comment here; I discussed pseudo-progression in another article.

A few other points to note:

1. DCVax-L did particularly well with patients with poor prognosis, like older patients, or those with substantial residual tumors, rGBM patients and so on, compared to ECP (external control population).

2. DCVax-L was well-tolerated. Of 2151 total doses of DCVax-L administered, only 5 serious adverse events were deemed at least possibly related to the investigational treatment. There were no immune rejection issues with the treatment.

3. DCVax-L could work well with other treatment modalities like checkpoint inhibitors for example.

About the trial, Linda Powers, CEO of NWBO, said:

We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax-L in this trial – particularly in the long tail of the survival curve, where we see more than double the survival rates as with existing standard of care. With well over 400 clinical trials for glioblastoma having failed over the last 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease.

Here’s some commentary from a Guardian article.

Financials

NWBO has a market cap of $1.2bn and a cash balance of just $11.7mn (current assets). Now that they published TLD, they will have triggered a $15mn loan facility. Plus, like I said before, Ms. Powers, the CEO, had offered a loan to the company before when it was in a much weaker position than now; I am guessing she can do so again, now that it is looking stronger. Last quarter, the company spent $7.8mn in R&D and $8mn in G&A – here. If they continue at that rate, there’s no cash; however, with the solid data that they have, they may be able to get cash, even through a market offering.

Risks

NWBO’s primary risks are two – lack of cash, and lack of clarity. I just discussed the cash problem. As for clarity, my previous coverages have touched on that. Like I grumbled in October:

If the company behaved like a normal company, announced official data, published, filed for approval – sued its detractors

It has published data now, so there’s a lot more clarity. The company now needs to sit down with analysts and be willing to take questions and so on – like it used to do earlier. They went into a dormant phase in the long years while their trial was running. Now that they have TLD, they need to come out of that phase and get vocal again.

Bottomline

NWBO went up over $2 in May when the company reported primary data at the New York Academy of Sciences. Now that they have their TLD in JAMA, the stock is just up to $1.15. This will be followed by an NDA, then PDUFA. Like all things NWBO, don’t expect a quick turnaround. However, things will start to move positively from here. Just a day before the publication, Sentinus, LLC took a large position in NWBO. Institutional interest is still quite low, at just .2%. I expect that to change as the company gains legitimacy. This would be a good time to buy the stock.

Appendix

Here’s the full list of authors:

Linda M. Liau, MD, PhD1; Keyoumars Ashkan, MD, FRCP, FRCS2; Steven Brem, MD3; Jian L. Campian, MD, PhD4; John E. Trusheim, MD5; Fabio M. Iwamoto, MD6,7; David D. Tran, MD, PhD8; George Ansstas, MD9; Charles S. Cobbs, MD10; Jason A. Heth, MD11; Michael E. Salacz, MD12; Stacy D’Andre, MD13; Robert D. Aiken, MD14; Yaron A. Moshel, MD, PhD14; Joo Y. Nam, MD15; Clement P. Pillainayagam, MD16; Stephanie A. Wagner, MD17; Kevin A. Walter, MD18; Rekha Chaudary, MD19; Samuel A. Goldlust, MD20; Ian Y. Lee, MD21; Daniela A. Bota, MD, PhD22; Heinrich Elinzano, MD23; Jai Grewal, MD24; Kevin Lillehei, MD25; Tom Mikkelsen, MD, FRCPC21; Tobias Walbert, MD21; Steven Abram, MD26; Andrew J. Brenner, MD, PhD27; Matthew G. Ewend, MD28; Simon Khagi, MD29; Darren S. Lovick, MD30; Jana Portnow, MD31; Lyndon Kim, MD32; William G. Loudon, MD33; Nina L. Martinez, MD34; Reid C. Thompson, MD35; David E. Avigan, MD36;Karen L. Fink, MD, PhD37; Francois J. Geoffroy, MD38; Pierre Giglio, MD39; Oleg Gligich, MD40; Dietmar Krex, MD41; Scott M. Lindhorst, MD42; Jose Lutzky, MD43; Hans-Jörg Meisel, MD, PhD44; Minou Nadji-Ohl, MD45; Lhagva Sanchin, MD44; Andrew Sloan, MD46; Lynne P. Taylor, MD47; Julian K. Wu, MD47; Erin M. Dunbar, MD48; Arnold B. Etame, MD, PhD49; Santosh Kesari, MD, PhD50; David Mathieu, MD51; David E. Piccioni, MD, PhD52; David S. Baskin, MD53; Michel Lacroix, MD54; Sven-Axel May, MD55; Pamela Z. New, MD56; Timothy J. Pluard, MD57; Steven A. Toms, MD58; Victor Tse, MD59; Scott Peak, MD59; John L. Villano, MD, PhD60; James D. Battiste, MD, PhD61; Paul J. Mulholland, MD62; Michael L. Pearlman, MD63; Kevin Petrecca, MD, PhD64; Michael Schulder, MD65; Robert M. Prins, PhD66; Alton L. Boynton, PhD67; Marnix L. Bosch, PhD67

And here are their affiliations:

• 1Department of Neurosurgery, University of California, Los Angeles

• 2King’s College Hospital, London, United Kingdom

• 3Department of Neurosurgery, Penn Brain Tumor Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia

• 4Division of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri

• 5Givens Brain Tumor Center, Abbott Northwestern Hospital, Minneapolis, Minnesota

• 6Columbia University Irving Medical Center, New York, New York

• 7New York-Presbyterian Hospital, New York, New York

• 8Preston A. Wells, Jr. Center for Brain Tumor Therapy, Division of Neuro-Oncology, Lillian S. Wells Department of Neurosurgery, University of Florida College of Medicine, Gainesville

• 9Department of Neurological Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri

• 10Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Medical Center, Seattle, Washington

• 11Taubman Medical Center, University of Michigan, Ann Arbor

• 12Neuro-Oncology Program, Rutgers Cancer Institute of New Jersey, New Brunswick

• 13Sutter Health, Sacramento, California

• 14Glasser Brain Tumor Center, Atlantic Healthcare, Summit, New Jersey

• 15Department of Neurological Sciences, Rush Medical College, Chicago, Illinois

• 16Department of Neurology, The Ohio State University, Columbus

• 17The Cancer Center of Columbus Regional Health, Columbus, Indiana

• 18University of Rochester, Rochester, New York

• 19University of Cincinnati, Cincinnati, Ohio

• 20John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey

• 21Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan

• 22Department of Neurology and Chao Family Comprehensive Cancer Center, University of California, Irvine

• 23Rhode Island Hospital, Providence

• 24Long Island Brain Tumor Center at NSPC, Lake Success, New York

• 25Department of Neurosurgery, University of Colorado Health Sciences Center, Boulder

• 26Ascension St Thomas Brain and Spine Tumor Center, Howell Allen Clinic, Nashville, Tennessee

• 27Mays Cancer Center at UT Health San Antonio, San Antonio, Texas

• 28Department of Neurosurgery, UNC School of Medicine and UNC Health, Chapel Hill, North Carolina

• 29The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire

• 30Advent Health, Kansas City, Kansas

• 31Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, California

• 32Division of Neuro-Oncology, Icahn School of Medicine at Mount Sinai, New York, New York

• 33Saint Joseph’s Hospital, Orange, California

• 34Jefferson Hospital for Neurosciences, Jefferson University, Philadelphia, Pennsylvania

• 35Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

• 36Beth Israel Deaconess Medical Center, Harvard Medical School, Cambridge, Massachusetts

• 37Baylor Scott & White Neuro-Oncology Associates, Dallas, Texas

• 38Illinois Cancer Care, Galesburg, Peoria

• 39Medical University of South Carolina Neurosciences, Charleston

• 40Mount Sinai Medical Center, Miami Beach, Florida

• 41Uniklinikum Dresden, Dresden, Germany

• 42Hollings Cancer Center, Medical University of South Carolina, Charleston

• 43Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida

• 44BG Klinikum Bergmannstrost, Halle, Germany

• 45Neurochirurgie Katharinenhospital, Klinikum der Landeshauptstadt Stuttgart, Stuttgart, Germany

• 46Seidman Cancer Center, University Hospitals–Cleveland Medical Center, Cleveland, Ohio

• 47Department of Neurosurgery, Tufts Medical Center, Boston, Massachusetts

• 48Piedmont Physicians Neuro-Oncology, Piedmont Brain Tumor Center, Atlanta, Georgia

• 49Department of Neuro-Oncology, Moffitt Cancer Center

• 50Pacific Neurosciences Institute and Saint John’s Cancer Institute, Santa Monica, California

• 51Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada

• 52UC San Diego Moore’s Cancer Center, La Jolla, California

• 53Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas

• 54Geisinger Neuroscience Institute, Danville, Pennsylvania

• 55Klinik für Neurochirurgie, Chemnitz, Germany

• 56Baptist Health System, San Antonio, Texas

• 57Saint Luke’s Cancer Institute, Kansas City, Missouri

• 58Departments of Neurosurgery and Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island

• 59Kaiser Permanente, Redwood City, California

• 60University of Kentucky Markey Cancer Center, Department of Medicine, Neurosurgery, and Neurology, University of Kentucky, Lexington

• 61Oklahoma University Health Science Center, Oklahoma City

• 62University College London Hospitals, London, United Kingdom

• 63Blue Sky Neurology/Neuro-Oncology, Englewood, California

• 64Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada

• 65Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York

• 66University of California, Los Angeles

• 67Northwest Biotherapeutics, Inc, Bethesda, Maryland