2023-03-21 11:49:00 ET
Summary
- Botensilimab is engineered for major improvements over earlier CTLA-4 agents.
- Melanoma, colorectal and pancreatic cancer Phase 2 trial enrollments should complete in 2023.
- An application to the FDA for commercial approval could come as early as 2024.
Agenus (AGEN) has developed a wide variety of antibody-based potential cancer therapies that are currently in clinical trials. Several are licensed to large-cap pharmaceutical companies. This article will concentrate on a single agent, botensilimab, which has been producing very impressive efficacy data in Phase 1 and Phase 2 trials for a variety of solid cancers. The latest update was at the Q4 2022 analyst conference on March 14. I will begin with the financials for Q4 from that conference before evaluating the potential for botensilimab.
Q4 2022 Agenus Results
In the Agenus Q4 2022 press release of March 14, 2023, GAAP revenue was reported at $28 million. $18 million of that was royalties from GSK ( GSK ) for QS-21 Stimulon, but it was non-cash because Agenus had received a large, upfront cash payment, from a third party, against future royalties. Net loss was $74 million, a greater net loss than the $68 million in Q4 2021, due to increased R&D expense for new trials. EPS loss was $0.24. Cash balances ended at $193 million, which provides a runway through Q2 2024. However, CEO Garo Armen emphasized that possible milestone payments or new deals with collaborators are likely to extend that runway.
Botensilimab mechanisms of action
Botensilimab is called an Fc-enhanced, anti-CTLA-4 antibody. The first approved CTLA-4 therapy was Yervoy (ipilimumab), a monoclonal antibody first approved by the FDA in 2011 for late-stage melanoma. It is now a common treatment, often combined with Opdivo, for a variety of solid tumors. Bristol-Myers ( BMY ) reported $568 million in Yervoy revenue for Q4 2022. Agenus had a CTLA-4 antibody, zalifrelimab, that appeared to be an improvement on Yervoy, but decided in 2021 to focus on developing botensilimab (AGEN1181). The Fc-region of this antibody has been engineered to engage with activating receptors on immune cells. It activates T cells, eliminates regulatory T cells, and establishes memory cells. The main difference with earlier CTLA-4 agents is its ability to work against cold tumors. Hot tumors typically have more mutations than cold tumors and naturally invoke a stronger immune response. First generation PD-1 and CTLA-4 agents typically work well against hot tumors but rarely against cold tumors. Botensilimab data to date indicate is works better than its predecessors against hot tumors, and also works well against at least some cold tumors. It can be administered as a monotherapy or in combination with a PD-1 agent like Agenus's balstilimab.
Botensilimab for colorectal cancer
The latest data for botensilimab for microsatellite-stable colorectal cancer was presented at the ASCO GI conference in January 2023. Botensilimab with balstilimab in heavily pretreated (multiple prior lines of therapy failed) MSS colorectal cancer showed an ORR (overall response rate) of 23% and a disease control rate of 76% for 70 patients. Patients in the trial had a median of four prior lines of therapy; 31% had received prior immunotherapy. The important comparison is with the other PD-1 + CTLA-4 combinations in similar patient populations. In those competing trials, response rates have been between 1 and 5%. For the Agenus combination, the 12-month overall survival rate was 63%, compared to a standard of care rate of just 25%. This shows why Agenus is eager to start a Phase 3 trial and is hoping the Phase 2 results may be sufficient to get an accelerated FDA approval.
Botensilimab for pancreatic cancer
While Agenus has said it began a Phase 2 trial in pancreatic cancer in late 2022, it has not released specific Phase 1 data for the pancreatic cohort. On Slide 26 [ March 2023 Agenus ], Agenus revealed it is targeting metastatic stage cancer with botensilimab in combination with chemotherapy. It states it has supporting data for clinical benefit from Phase 1. It also shows the comparison will be standard of care for second-line therapy, where the current OS is 7 to 8 months and the ORR is under 15%. Because pancreatic cancers tend to be discovered only when they are advanced, the prognosis for most patients is for brief survival.
Botensilimab for melanoma
In a September 2022 release , Agenus announced it has initiated a Phase 2 trial of botensilimab as a monotherapy for advanced refractory melanoma. Patients had to have failed a prior PD-1 therapy with or without a CTLA-4 therapy. It stated the melanoma cohort from the Phase 1 trial demonstrated remarkable activity but did not release specific data. It is also testing botensilimab in combination with a CD137 antibody, AGEN2373, for this indication. It hopes botensilimab or the combination will demonstrate superiority to Yervoy.
Botensilimab for other solid tumors
Agenus presented Phase 1 clinical data for several cancer types for botensilimab at SITC 2022 . Though results were promising in each case, these types were not selected for the first Phase 2 clinical programs. The results were for botensilimab with balstilimab. In ovarian cancer, there was a 26% overall response rate, including one complete response. The disease control rate was 63%. In sarcoma, there was one complete response with a 42% overall response rate and 67% disease control rate. In NSCLC (non-small cell lung cancer), with just 5 patients at data cut-off, the overall response rate was 60% and disease control rate was 80%. In all the trials, the patients were relapsed/refractory, usually having failed multiple lines of therapy. The sample sizes from these trial cohorts were small.
Analysis
Agenus stock took a hit when a competing approval for Merck ( MRK ) effectively blocked the Agenus path forward for balstilimab in cervical cancer in 2021 [See Agenus provides update on balstilimab development ]. After an event like that, investor psychology tends to be negative and overlook the positive future possibilities of a company.
2023 objectives for Agenus include completing enrollment in the Phase 2 colorectal, melanoma, and pancreatic cancer studies. Agenus also hopes to launch a Phase 3 study in colorectal before the year ends, but hopes to make a submission to the FDA in 2024 based on Phase 2 data. Agenus appears grossly undervalued if it is assumed that botensilimab will be approved and eventually generate Yervoy-type revenue. Some level of discounting should be allowed for the possibility of failing to receive regulatory approval. Even if approved, it might be hard to take market share from Yervoy in hot tumor types, where doctors may tend to be conservative if the response rates are not that different. In hot tumors, botensilimab will likely be tried, at first, only if Yervoy fails. But that is likely to be the label anyway, as the current trials are being conducted on patients who have failed multiple lines of therapy. Typically, after an initial approval, Agenus would start working on label expansion of two types: bringing it to earlier lines of therapy, and bringing it to other types of cancer.
Valuing Agenus can be done conservatively, assuming a high probability of failure at some point in the trial and commercialization chain of events. While risks remain, I believe the data to date have removed much of the risk. Lumping together all the patients from all the botensilimab trials, the sample size is now over 300 patients. For good measure, throw in some value for the rest of the pipeline, including partnerships with Merck, Gilead (GILD), and Incyte (INCY). Agenus closed at $1.64 of March 20. That gave it a market cap of $565 million. While we will have to wait until 2024 for the crucial data to be reported, most likely it will line up with the data that has already been presented. That means Agenus is likely to have the most effective CTLA-4 agent on the market in 2024 or 2025.
For further details see:
Agenus Readies Comeback With Impressive Botensilimab Data