Can Imugene save Big Pharma from their product restrictions,...

Can Imugene save Big Pharma from their product restrictions, regulatory and safety issues?

1. Cf33/Vaxinia opens the door to solid tumour treatment

Couple of things to focus on when following Imugene (IMU - ASX). On their own CAR T’s and allogenic therapies have ostensibly been successful in treating blood borne cancers such as lymphoma’s, leukaemia and non Hodgkins lymphoma. Yet when combined with CF33/Vaxinia and Imugene’s Oncarlytics arm, Car T’s and allogenic therapies have illustrated benefits for cancer patients with solid tumours, including significant solid tumour killing. Therefore when it comes to Big Pharma, Imugene’s strongest value proposition rests in CF33/Vaxinia’s ability to not only treat solid tumours as a monotherapy, or in combination with MAB’s (i.e., Keytruda), but as the driving force between linking allogenic therapies and Car T’s to the broad array of solid tumours present in approximately 90% of all cancer diagnosis.

Hence despite the fact that on their own allogenic therapies, Car T’s, ADC’s and even MAB’S do offer benefits to cancer patients, they are predominantly restricted in the main to 10% of all cancer patients, those suffering from blood cancers. CF33/Vaxinia and Oncarlytics effectively open the door through combination to target the broader array of solid tumours such as liver, pancreatic, bile duct, colorectal, brain, ovary, breast and colon cancers.

It must be noted that successful immunotherapies such as Keytruda, Opdivo and Herceptin have all succeeded in treating solid tumours over and above the standard of care (SOC) chemotherapy. In factwww.ncbi.nlm.nih.gov/pmc/articles/PMC6503308/ notes Monoclonal antibodies (mAbs) have become a cornerstone in the therapeutic guidelines of a wide range of solid tumors. The targeted nature of these biotherapeutics has improved treatment outcomes by offering enhanced specificity to reduce severe side effects experienced with conventional chemotherapy.

Notwithstanding, poor tumor tissue penetration and the heterogeneous distribution achieved therein are prominent drawbacks that hamper the clinical efficacy of therapeutic antibodies.

2. What about NP’s and ADC’s in combination with MAB’s?

Speaking of the inadequate tissue penetration NP’s or Nanoparticles as well as Anti Drug Conjugates (ADC’s) have been utilised to penetrate cell tissue and deliver much needed immunotherapy to solid tumour patients. Nanoparticle delivery vehicles can play a role in multiple steps of activation of immune system to suppress cancer. Nanoparticle-based therapeutics can induce tumor cell death and in turn increase neo-antigen release from this tumor. Nanoparticles can be utilised to improve antigen presentation and T cells activation. Yet despite acute delivery systems, solid tumours possess strong resistance mechanisms to stave off the effect of monoclonal antibodies. Whilst perhaps of bigger concern is that some of the monoclonal antibody delivery instruments such as anti drug conjugates (ADC’s) exhibit safety concerns for solid tumour patients. As such safety concerns inherent to the high potency and structural versatility of ADCs and NPs have been prominent barriers in their implementation.

CF33/Vaxinia has been shown now to turn tumours from cold to hot, and in doing so penetrate solid tumor tissue, with little or no side effects. In fact CF33/Vaxinia founder Professor Yuman Fong has suggested “Once Vaxinia infects a solid tumour, it works” . Further to which we now know “it works” without the side effects and toxicity associated with other treatments such as MAB’s and their associated delivery mechanisms including NP’s and ADC’s.

3. So what does this all mean with respect to Imugene and the road ahead?

In essence Imugene has pulled the right rein in purchasing and establishing their own off the shelf, targeted strategy to tackle cancers such as lymphoma, through their acquisition of Oncarlytics and now Azer Cel. Yet as stand alone vehicles the treatment of solid tumours is not yet possible without the addition of CF33/Vaxinia. Therefore if found to be successful in obtaining positive immune responses, including tumour regression, rest assured CF33/Vaxinia shall stimulate significant IMU share price appreciation within a heart beat, as CAR T, allogenic therapy providers and investors seek to acquire a piece of the keys to the kingdom, that being the predominantly untouched solid tumour market. Added to which CF33/Vaxinia has expressed only limited side effects in patients, including a few flu like symptoms. This a massive feather in the cap of Professor Fongs viruses, as their low toxicity offers huge appeal for an oncology world hungry for drugs with fewer patient side effects.

There is much riding on the current expanded Vaxinia MAST Trial. Late stage cancer patients whose cancer has spread in many instances to the nether regions within their body are hanging on for dear life in the hope Vaxinia itself shall spread and circumvent the disease from advancing even further, cutting it off at the pass as it were. But aside for the Vaxinia MAST Trial Imugene does have another toe in the water. 52 patients are currently being enrolled and dosed in A Phase I, Dose Escalation and Dose Expansion, Safety and Tolerability Study of onCARlytics (CF33-CD19), Administered Intravenously or Intratumorally in Combination With Blinatumomab (BLINCYTO) in Adults With Advanced or Metastatic Solid Tumors (OASIS). Developed by Saul Priceman M.D. of the City of Hope cancer research facility in the US Oncarlytics has proven effective pre clinically in targeting solid tumours through the expression of CD19, without the high potency and safety concerns of NP’s and ADC’s (see above).

4. MAB’s and CAR T’s have limitations. They are expensive and produce side effects in cancer patients

Nivolumab (Opdivo, Bristol Meyer Squibb, NY) and pembrolizumab (Keytruda, Merck, NJ) were the first two US Food and Drug Administration (FDA)-approved monoclonal antibodies (mAb’s) targeting programmed death-1 (PD-1). Since then therapeutic monoclonal antibodies (mAbs) have been the fastest growing class of new therapeutic molecules, holding great promise for the treatment of a variety of diseases, including chronic inflammatory diseases and cancer. Monoclonal antibodies are given intravenously (injected into a vein). Though as cancer.org notes the antibodies themselves are proteins, so giving them can sometimes cause something like an allergic reaction. This is more common while the drug is first being given.

Possible side effects can include:

• Chills
• Weakness
• Headache
• Nausea
• Vomiting
• Diarrhoea
• Low blood pressure
• Fever
• Rashes

Compared with chemotherapy drugs, naked mAbs tend to have fewer serious side effects. But they can still cause problems in some people. Some mAbs can have side effects that are related to the antigens they target. For example:

• Bevacizumab (Avastin) is an mAb that targets a protein called VEGF that affects tumor blood vessel growth. It can cause side effects such as high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.
• Cetuximab (Erbitux) is an antibody that targets a cell protein called EGFR, which is found on normal skin cells (as well as some types of cancer cells). This drug can cause serious rashes in some people

Nb. See https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/monoclonal-antibodies.html#:~:text=Some%20mAbs%20can%20have%20side,blood%20clots%2C%20and%20kidney%20damage for more

Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) were the first two CAR-T products to be approved for the treatment of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (ALL) and adult patients with relapsed or refractory diffuse large B-cell lymphoma. Yescarta originally had significant neurological side effects in the initial patients trialled, even fatalities, so, in 2017, NCI researchers tweaked their original CAR T-cell design with the goal of creating a safer and more effective therapy. Results from the first clinical trial of the remodeled CAR T cells caused far fewer neurologic side effects than the original therapy did in an earlier trial, yet it was equally effective. The findings were reported January 20 this year in Nature Medicine.

Nb. See https://www.cancer.gov/news-events/cancer-currents-blog/2020/car-t-cell-therapy-lymphoma-reduced-side-effects#:~:text=One%20issue%20with%20current%20CAR,destroy%20the%20CAR%20T%20cells for more.

Though once again despite new studies revealing that patients with blood cancers experienced a significant improvement in their reported well-being six months after receiving CAR T-cell therapy, The American Cancer Society notes that as CAR T cells multiply, they can release large amounts of chemicals called cytokines into the blood, which can ramp up the immune system. Serious side effects from this release can include: high fever and chills and trouble breathing. Further to which people with low white blood counts could remain at increased risk of infections for some time.

5. The FDA puts CAR T’s under the microscope

While as noted above the benefits of these CAR T-cell therapies continue to outweigh the potential risks for their approved uses, it seems the long-term impact of the treatment still needs to be evaluated. Patients and clinical trial participants receiving treatment with these products need to be monitored life-long for new malignancies. Recently the FDA launched an investigation into all of the six CAR T products they approved for sale in the US. yahoo.com published today the investigation comes on the heels of reports received by the FDA of T-cell malignancies in patients who received treatment with BCMA- or CD19-directed autologous CAR T-cell immunotherapies. The malignancy resulted in not just hospitalisation of patients but, in certain cases, death. These reports came from ongoing clinical trials and/or post marketing adverse event (AE) data sources. The agency has determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies.

6. Combining Imugene’s CF33/Vaxinia with MAB’s and CAR T’s could provide regulatory authorities with a solution to higher drug costs and patient side effects

In spite of these setbacks found in the delivery of MAB’s and more recently CAR T’s, they are here to stay. cancercentre.com noted that a 2023 study published in April in Nature Reviews Clinical Oncology showed complete response rates of 40 percent to 54 percent for relapsed and/or refractory aggressive B-cell lymphomas, 67 percent in patients with mantle cell lymphoma, and 69 percent to 74 percent in patients with indolent B-cell lymphomas.Therefore CF33/Vaxinia’s ability to combine with MAB’s and CAR T’s could be crucially important to Big Pharma, in order to find safer more cost effective solutions to administer MAB’s and CAR T’s whilst at the same time appease regulatory authorities and governments in the US. High costs of patient delivery, over $250,000 USD per patients in many instances, and excessive side effects (see above) are wreaking havoc with BP, who are constantly having their MAB’s and CAR T candidates thrown off the FDA approved lists due to these limitations.The recent CAR T news has not assisted Big Pharma on little bit, to say the least.

If Keytruda can prove efficacious in combination with Vaxinia in the current MAST Trial, and if BLINCYTO can prove efficacious in its current combination trial with CF33/Vaxinia and Oncarlytics, Imugene shall go a long way toward garnering interest from Big Pharma. Blincyto already has runs on the board. Recently after 3.5 years of follow-up from a Blincyto Trial , 83% of patients in the Blincyto combo arm of Blincyto and chemotherapy were still alive. That compared with 65% in the chemo-only group. That said recent CAR T consternation and investigations from the FDA render Imugene’s CF33/Vaxinia and Oncarlytics safety record even more valuable, to all those wishing to combine with them.

7. Maybe the CAR T investigation announced today could awaken Big Pharma them their slumber.

Clearly Imugene’s safety profile has already garnered the interest of regulatory authorities in the US. The FDA recently approved the aforementioned CF33/ Vaxinia/Oncarlytics/BLINCYTO Trial with an FDA IND in rapid time, and this week agreed to afford a Fast Track designation and Priority Review for Vaxinia’s treatment of bile duct cancer in the now expanded Vaxinia MAST Trial. They are not sitting on their hands and knees waiting for the grass to grow under their feet.

Perhaps its only Big Pharma who fail to comprehend what’s at stake here. Perhaps it’s only them sitting back and waiting for things to happen. But if I were them, when it comes to CF33/Vaxinia, I wouldn’t be waiting too much longer.

DYOR Seek investment advice as and when required Opinions only