B-vaxx - a sleeper surprise?

Good morning all.

A week ago I mentioned that I would do a bit more reading on B-vaxx and report back. B-vaxx is seldom mentioned in IMU announcements and it gets little coverage generally, but it is approaching the end of a Phase 2 clinical trial and, as investors or potential investors, readers of Hot Copper may be interested in the potential of B-vaxx for IMU. This is my analysis. It has taken a while but I was also waiting for all the excitement of last week to calm down a bit.

Apologies to those who hate a new thread. As one of the three drugs in Clinical trials for Imugene, and arguably the most advanced, I think B-vaxx deserves to have its own thread. So there. J

Warning: Proceed beyond this point at your own risk. This is a very long and probably quite tedious review of what we know about B-vaxx, with some added comment from me. Before going further please do consider that you may have far better things to do with your time. I hope you do!

No? Well - you have been warned....

Along with PD1-vaxx, B-vaxx is one of the drug candidates developed by Prof Pravin Kaumaya at the University of Ohio, which came to the attention of Imugene in 2018 just as they were about to develop their own PD1 B-cell vaccine. However B-vaxx was already quite far advanced at that point and indeed the Phase 1 dose escalation trial for B-vaxx started way back in June 2011, which long predates the 7/6/18 licencing deal with Imugene. By the time that deal was done, B-vaxx was already well into a Phase 2 trial. So in a sense Imugene "inherited" B-vaxx as part of the 7/6/18 deal and it has been bubbling along in the background with little extra to do, and therefore with minimal profile - but I think we should all be more interested.

The results of the Phase 1 dose escalation were summarised in Feb 2019 (though the print version came later in June 2019) as follows:

Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.

Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Sources:

https://hotcopper.com.au/threads/ann-clinical-cancer-research-journal-publish-b-vaxx-phase-1-data.4652239/

https://clincancerres.aacrjournals.org/content/25/12/3495

There are a few things to note about this:

Excellent safety/low toxicity:

This was only a Phase 1 trial so it was primarily designed to identify any toxicity and determine the “optimal biologic dose” (OBD) for use in a Stage 2 trial. As they put it in the AACR paper: “the phase I studies are not designed to test efficacy of experimental therapy but to establish safety profile and best dose of the therapy.“

In that respect the trial was a total success. Of the three dosage levels trialled, dosage 2 (mid range) was found to be the OBD for use in further trials. Note – this NOT because of toxicity at dose level 3. It was simply because the patients on dosage level 2 performed better than those on dose level 3. With regards to toxicity, the researchers have this to say:

“The vaccine was well tolerated overall, with minimal or no toxicities in most patients. No DLTs were observed. The most common toxicities at least possibly related to study treatment were injection-site reactions (grade 1–2 in 24% of patients). Grade 2 buttock hematoma developed at the site of the injection in 1 (2%) patient. Additionally, 2% of patients developed grade 2 systemic allergic reaction (mild hypotension and diaphoresis). Grade 1 rash also developed in 2% of patients.”

They point out that this compares extremely favourably with the T-cell MAb alternatives which dominate the market:

“The study vaccine bypasses the disadvantages of passive immunotherapy with monoclonal antibodies, i.e., high cost and the need for repeated treatments that can result in serious toxicities, such as hypersensitivity reactions, cardiomyopathy, and, in rare cases, pneumonitis. Our peptide vaccine was not associated with an increased risk of cardiomyopathy, despite sustained production of endogenous, fully human antibodies that function very similarly to trastuzumab and pertuzumab. Peptide cancer vaccines are an attractive therapeutic option as they are safe and easily manufactured and administered. Additional advantages of peptide cancer vaccines are exquisite specificity, low toxicity, and the potential for a durable treatment effect due to immunologic memory.”

Phase 1 Trial patients were NOT selected for treatment effectiveness:

The researchers were also looking for immune responses and therapeutic benefit, but because it was only Phase 1 trial and their main focus was toxicity and OBD, the selection criteria they used for the dose escalation arm actually reduced their chances of getting good effectiveness data.

How so? Well….

As Imugene’s own website explains, “Similar to HER-Vaxx, B-Vaxx is a B-cell immuno-therapy designed to treat tumours that over-express the HER-2/neu receptor.”

So B-vaxx (like Her-vaxx) is intended to help Patients who have a cancer with a high level of over expression of Her-2. If your cancer does not over express the HER-2 receptor, then B-vaxx is unlikely to be effective. (In one sense, this is an advantage of B-vaxx and Her-vaxx. Her-2 positive cancers tend to be more aggressive and harder to treat with chemo. Market leading MaB drug Herceptin is also designed to treat Her-2 positive cancers).

However – because they were mainly interested in toxicity - the selection criteria for the Phase 1 trial allowed for the inclusion of patients who quite possibly did NOT have HER-2 over expression. The trial selection criteria state: “Patients are not required to have HER-2 over-expression to be on this study.” Source: https://clinicaltrials.gov/ct2/show/NCT01376505

The consequence of this is: when looking at the effectiveness data for the Phase 1 trial we need to bear in mind that almost certainly some of the patients (we have no way of knowing how many) did not have a cancer which over expresses Her-2 and they were therefore never likely to receive any therapeutic benefit from B-vaxx.

But the trial participants were definitely extremely unwell:

The very first inclusion criteria for the trial says it all: “Must have histologically confirmed metastatic solid tumor; the malignancy should be considered incurable using standard treatment.” The Phase 1 trial results paper also add “metastatic”: “Eligible patients were required to have the following: (i) metastatic, incurable solid tumor malignancy,

So these patients were “incurable” – with a severe cancer which was already spreading to other parts of their body (ie metastatic).

So Who did get included?

From the Phase 1 study results paper: “Forty-nine patients were determined to be eligible for the study and received at least 1 dose of study vaccine (N = 8, 9, 20, 12 in cohorts 1–4, respectively; see Supplementary Table S1). The study population consisted of subjects with a wide range of different malignancies. The median age of patients was 59 (range, 35–81), with a majority of patients having received ≥4 prior lines of therapy”

From which we can say:

They were all very sick people, diagnosed as incurable. Most of them had tried at least 4 other types of treatment. Again – when looking at the effectiveness data – all of these patients were terminal, most had tried 4 or more other types of treatment and some probably never had a cancer appropriate for treatment with B-vaxx anyway.

So to the results:

“Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.”

There were 49 patients who started the trial, but only 35 completed the 3 required inoculations. The 14 who dropped out are not included in the results. It is reasonable to assume that those who dropped out were simply to ill to continue, or died before completion.

“Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.”

So 16 out of 35 seemed to obtain some therapeutic benefit – which seems actually quite good to me, given the severity of disease required for inclusion in the trial, and the number of other treatments they had all been through.

The study authors highlight this fact with regard to “Patient 2c” – who despite having extremely severe illness responded very well to treatment over 3 years – possibly because he had NOT received prior chemo and therefore “his immune system was very much intact.” The full text regarding patient 2c is deeply interesting:

“Patient 2C travelled to Columbus, Ohio, from Seattle, Washington, to receive his first vaccine on May 30, 2012, and two boosters at 3 weeks apart. The patient returned every 6 months through December 10, 2015, to receive the 7 booster vaccinations, spanning 3.5 years. Prior to enrolment in our study, this patient was diagnosed with T2N2bM0 poorly differentiated carcinoma of the right parotid gland and underwent radical parotidectomy and selective right neck dissection. The surgical pathology revealed 25 lymph nodes positive for metastatic disease. Interestingly, the tumor also had "patchy foci" of 3+ Her2/neu staining based on IHC on a background of equivocal 2+ positivity. Recurrence was discovered in the right axillary lymph nodes about 2 years later and the patient underwent right axillary lymph node dissection, which revealed that four of 46 lymph nodes were positive. He was subsequently enrolled in our study. The exceptional response in this patient may also be due to the fact that this patient did not receive any chemotherapy prior to enrolment. Thus, his immune system was very much intact and likely more responsive to vaccine treatment. This is an important fact as the vaccine therapy should be more effective in such patients.”

Source: https://clincancerres.aacrjournals.org/content/25/12/3495

In a later article, summarising the history of B-cell immunotherapy, Prof Kaumaya revisits the B-vaxx Phase 1 trial and he makes this highly encouraging comment:

“One HER-2-positive patient received seven 6-monthly booster vaccinations suggesting that B-cell vaccination does not result in resistance to therapy as is well documented for other HER-2 therapies. A majority of the patient antibodies showed potent antitumor activity.”

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426751/

Now to the Phase 2:

The extension cohort for Phase 2 started enrolments in October 2016 and they also were very very sick patients! As well as being “incurable with standard treatments” and suffering from metastatic cancer, the selection criteria include:

• Histologically documented metastatic or unresectable breast, ovarian and gastrointestinal cancers

• Progressive disease after at least one line of standard therapy

• Patients must have received or refused first line standard systemic therapy for their metastases (if applicable)

• Patients (pancreatic and esophageal cancers) must have received no more than two prior cytotoxic chemotherapy regimens in the last two years after standard therapy. Patients (breast and gastrointestinal cancers) must have received no more than three prior cytotoxic chemotherapy regimens in the last two years after standard therapy.

https://clinicaltrials.gov/ct2/history/NCT01376505?V_12=View#StudyPageTop

In the October 2016 clinical trial update, and again in the June 2017 update, the Study Completion date was expected to be December 2017:

https://clinicaltrials.gov/ct2/history/NCT01376505?V_12=View#StudyPageTop

https://clinicaltrials.gov/ct2/history/NCT01376505?V_13=View#StudyPageTop

However, that clearly didn’t happen. In an April 2018 update the expected completion date was pushed back to December 2018: https://clinicaltrials.gov/ct2/history/NCT01376505?V_14=View#StudyPageTop

But that didn’t happen either, and a further trial update in July 2019 pushed the trial completion date back to 31 December 2021. https://clinicaltrials.gov/ct2/history/NCT01376505?V_15=View#StudyPageTop

So the Phase 2 trial for B-vaxx has now been running for at least 4.5 years, with completion not expected before the end of this year.

We cannot draw any definite conclusions from that but I think it is fair to reflect on comments that Leslie Chong herself has made several times with regard to the Her-vaxx Phase 2 trial. The longer it takes, the better the news, because it means that at least some of the trial patients are still alive – presumably because the treatment is helping.

We DO know – from Prof Kaumaya’s 2020 article on the history of B-cell immunotherapy – that the Phase 2 trial DOES ensure that patients are selected for Her-2 over expression:

“Given the initial promise, continuous development of the vaccine is ongoing in a Phase II trial at the suggested optimal biological dose (OBD) in a less heavily pretreated patient population in breast and/or gastrointestinal malignancies with HER-2/EGFR overexpression.”

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426751/

Summary and Conclusions:

The B-vaxx trial receives very little mention from Imugene but it could be the “sleeper cell surprise” in their already impressive drug pipeline.

The Phase 1 trial again shows the apparent low toxicity of B-cell immunotherapy. We know how important that is, given the side effects of current market leading MaB treatments, let alone the horrors of chemotherapy.

The Phase 1 trial results were not spectacular with regard to clinical effectiveness/therapeutic benefit but we need to view that in context:

• All patients were terminal and horribly unwell with severe metastatic cancer
• B-cell immunotherapy relies on the patient having an effective immune system but all patients had been heavily pretreated – most of them with SOC chemo likely to damage their immune system
• Patients had NOT been screened to ensure that all had a cancer with HER-2 over expression, so it is likely that some of the patients were simply not appropriate candidates for treatment with B-vaxx.
• Despite the above limitations nearly half the patients who completed the three inoculations did show some benefit, and one patient who had not received chemo, and whose cancer was definitely Her-2 over expressing did extremely well.

We also know that the Phase 2 trial is better designed and more likely to produce clinical benefit because the patients are “less heavily pretreated” and they HAVE been screened to ensure that they have a cancer with Her-2 over expression.

Combine that with the fact that the Phase 2 trial is still in progress after 4 and a half years. I think that gives us reasonable grounds to conclude that the Phase 2 trial of B-vaxx – although somewhat “under the radar” – may just surprise us to the up side.

It is worth bearing in mind that when Prof Kaumaya and colleagues decided to test Pd1-vaxx in mice as a combination therapy, the combination drug they chose to use it with was B-vaxx.

And the results were good.

https://pubmed.ncbi.nlm.nih.gov/33117602/

Disclaimer:

I do not have qualifications or expertise in this field. My comments are in the category of “interested amateur” and should not be taken as advice. I have cited my sources but I can easily be wrong or simply misguided and I recommend you do your own reading, draw your own conclusions and definitely make your own decisions with regard to investment.

If you have read this far I also suggest you go for a walk in a forest, or somewhere near the ocean, for at least an hour or two. Leave your phone behind.

Cheers

Dave J