Media Thread, page-8652

The mRNA thought got me thinking about the other tech in the space and the recent deals from BPs around Antibody drug conjugates or ADCs. Since the two largest deals in the BP space have been around ADC’s it is possibly the best place to start to compare what IMU has and its commercial viability i.e. saleability. Seagen had four approved ADCs with clinical studies underway to bolster the indications before being bought out by Pfizer for $43 billion. They also generated $2 billion in revenue and have a significant depth to their business (2000 employees). Immunomedics was close to approval for their drug Sacituzumab govitecan before being bought out for $21 billion. All of this is to say that comparing Imugene with these two wouldn’t be an apples-to-apples comparison, however, comparing their therapy’s initial results could shed some light on the value IMU has in its pipeline should we achieve the same or similar or better.

Background on ADCs

ADC’s or antibody-drug conjugates are monoclonal antibodies (like a Keytruda, Herceptin, or atezolizumab) with a chemotherapy payload. Think of a Trojan horse being allowed in the tumour and the chemo being the thing in the horse and getting released. Targeted chemo (a very simplistic way to describe it). Chemotherapies are very powerful cancer killers, however, they are also very toxic to healthy cells and organs as well as having significant side effects, often leaving the patient with long-standing issues. So, a therapy combining the targeted nature of monoclonal antibodies while lending that tumour specificity to powerful chemo agents has obvious value. Although, they do have a similar drawback to most cancer therapies in that they can be highly toxic with similar safety concerns as chemo (as often the chemo can be released outside the tumours).

Given that ADCs primary mechanism is via a monoclonal antibody; their chemo payload is only as good as the effectiveness of the monoclonal target is at infecting cancer, which ranges in success rate depending on the indication and cancer type. Not to be crass but to explain the success rates and indications would be like measuring cancers in terms of their ‘intelligence’. The smarter the cancer type/indication/location, the better it is at evading our immune cells, replicating, and hiding from other therapies. Thus, unfortunately, the more deadly and formidable it is from a treatment perspective (detectability also is a big factor). In turn, the lower the 5-year survival rate (as a %) for that indication is. The lower the survival rate, the harder it is to ‘outsmart’ these cancers and thus the greater need to find therapies to treat these deadly cancer types (or find them earlier).

Some info of 5-year survival rates are below (cancers are grouped based on organ/location only and not indication such as HER2 TNBC etc):

https://www.nuffieldtrust.org.uk/resource/cancer-survival-rates#:~:text=The%20cancers%20with%20the%20lowest,and%20prostate%20cancer%20(88%25).

In the trial that led to the approval of Immunomedics main therapy, Sacituzumab govitecan (Trodelvy), the results in TNBC were (see here for journal):

The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies. Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anaemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).

One of the most effective ADC treatments seems to be Brentuximab vedotin (owned by Seagen) which is used to treat advanced Hodgkin’s Lymphoma (survival 5-year survival 89%). The initial study within a subset of HL the therapy was used with chemo and resulted in 24 complete responses out of 25 patients. An amazing result for patients that were very advanced and had numerous lines of treatment prior.

A subsequent study in combination with chemo led to its approval and had the following results (see here):

Efficacy was based on independent review facility-assessed progression-free survival (PFS), defined as time from randomization to progression, death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease. The median PFS was 48.2 months (95% CI: 35.2, not estimable) for patients on the brentuximab vedotin + CHP arm and 20.8 months (95% CI: 12.7, 47.6) for those on the CHOP arm (hazard ratio 0.71; 95% CI: 0.54, 0.93; p=0.011). The most common adverse reactions (incidence ≥ 20%) observed ≥ 2% more in patients receiving brentuximab vedotin + CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy occurred in 52% of patients on the brentuximab vedotin + CHP arm and 55% on the CHOP arm.

Another ADC also approved and in Seagens stable achieved the below on bladder cancer (5-year survival 54% & 10th most common cancer) (see here):

Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti–PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients.

ADCs are promising therapies with much scope to improve, so it’s no surprise they have attracted billions. One of the shortfalls of ADCs is that they don’t lend themselves as much to combinations due to overlapping toxicities with other therapies (see here). Although CF33 looks like hot property now, our B-Cell platform could potentially have a similar scope to ADCs are adding to BP depth now, so I am certainly looking forward to more data being released there. Of note from the above trials are the response rates in the patient population. They give a good indication of some expectations around what is deemed a clinical success. One of the therapies achieved 3 complete responses and 33 partial in TNBC from 108 patients. Also, note some of the adverse reactions (and some deaths) from the treatments. When we get our initial readout for Check-Vacc, it would be a good comparison to see how CF33 stakes up, I'm quietly confident.

Ultimately, it should be becoming apparent now how significant it is that IMU has extremely safe therapies, the lengths BP will go to and the amount of money they will pay for therapies leading to better outcomes across multiple illnesses.