A day after I covered Agenus Inc. (NASDAQ:AGEN) in a positive article on July 4, there was a 20% rally, and, as Seeking Alpha says, it posted the best intraday in 13 months. The stock is up 23% in the last few months. Data announced at SITC from a 125 patient phase 1 study of botensilimab and balstilimab combo in a basket of solid tumors was also positive, with three complete responses. That has been the news since July.
I have discussed earlier how research companies have a bad habit of putting their worst foot forward. They will spend time and money trialing the earliest molecule to come out of their lab, only to realize, years later, that their second, or third, or nth molecule is the better one. By then, nobody would be interested. This happened with TG Therapeutics (TGTX), and this is also happening with Agenus.
In my July article, I noted how the company managed to pull itself away from the brink of disaster by posting strong data from 1181 after withdrawing a BLA last year for balstilimab monotherapy in 2nd line cervical cancer. 1181 is the company’s next generation CTLA-4 agent, AGEN1181 or botensilimab.
In an earlier article, I discussed why they pulled the BLA even after getting a PDUFA date last year, and how the FDA’s alleged big pharma favoritism could have played a role in the FDA’s sudden approval of Merck’s Keytruda just before Agenus’ PDUFA. However, balstilimab may work better in the 2nd line cervical cancer setting as a combo therapy, and the market, anyway, is small. So pulling the BLA may have been a blessing in disguise for the company, saving them some money, since they also stopped the then-ongoing trial.
Interestingly, Agenus has not abandoned the 2nd line cervical cancer indication, where we now have Keytruda and also Libtayo from Sanofi and Regeneron. Libtayo’s situation mimics balstilimab’s; in January this year, the two companies pulled Libtayo’s application because they could not “align with the FDA” on certain post-marketing studies. However, Libtayo continues to post solid data from the program, most recently at ESMO in September, where they showed a 31% OS survival benefit over chemotherapy. One difference between Libtayo and balstilimab is that while Libtayo demonstrates clinical benefits like survival, balstilimab is looking at biomarkers.
So Agenus has just moved away from balstilimab monotherapy, but 2nd line cervical cancer is still their most advanced indication, and the second component of the combo is Zalifrelimab, a CTLA-4 inhibitor. The combination, naturally, is called bal/zal, and they are in the phase 2 stage. Last year, I provided phase 2 data from this program. There doesn’t seem to be a phase 3 listed. The phase 2 program produced some good data, like I said, however Libtayo’s survival data is stronger.
I should note that while bal/zal in 2nd line cervical is their most advanced program, the company said time and again that botensilimab is their main asset, and therefore, programs that include botensilimab are its main programs. As I noted earlier about this molecule:
[Botensilimab is]...an Fc-enhanced CTLA-4 inhibitor. Fc enhancement allows for broader coverage of the molecule, increasing by 40% the targeted patients, as well as increasing benefits for existing patients. Some of the benefits are T cell priming, Treg depletion, and T cell memory formation as well as improved safety.
Botensilimab has consistently produced good data. Last year, at SITC, Agenus presented data from a 100-patient basket study which I referred to earlier. The molecule reported clinical activity in heavily pretreated patients with 9 cold, treatment-resistant tumors as monotherapy and in combination with balstilimab. The molecule also avoided some of the safety issues f first generation CTLA-4 molecules, like hypophysitis, pneumonitis, or high-grade hepatitis.
Botensilimab has kept adding notches to its achievements, with positive early-stage data for botensilimab and balstilimab combination in patients with microsatellite stable or MSS colorectal cancer. MSS-CRC is a difficult to treat cancer, occurring in up to 85% of CRC patients. MSI-LOW and MSS CRC have even fewer options, and this is where Botensilimab produced solid data.
In November this year, at SITC, the bal/bot combo presented data from a phase 1 trial in treatment-unresponsive metastatic solid tumor patients. There were 125 evaluable patients in four cancer types: microsatellite stable colorectal cancer (MSS-CRC), recurrent platinum refractory/resistant ovarian, sarcoma, and PD-(L)1 relapsed/refractory non-small cell lung cancer (NSCLC). There were one complete response each in sarcoma, ovarian and MSS-CRC. The overall response rates for MSS-CRC, R/R ovarian cancer, sarcoma, and R/R NSCLC stood at 22%, 26%, 42%, and 60%, respectively.
Out of 59 patients in MSS-CRC, there was one CR, 12 PRs, 20 Stable disease and 16 progressive disease patients. Disease control rate was, thus, 73%, which is a good achievement in such treatment-refractory patients. Median duration of treatment was not reached at the time of data cutoff. 12 month OS was in 60% patients, and median PFS was 4.1 months. Median OS was not reached at cutoff. There were 22 PRs among all patients.
Three phase 2 studies are underway using Botensilimab in MSS-CRC, PD-1 r/r melanoma, Pancreatic (w/chemo) and PD-1 r/r melanoma in combination with CD137 directed AGEN2373.
AGEN has a market cap of $737mn and a cash reserve of $218mn with revenue of $22.8mn. Cash used in operations was $32mn, with R&D expenses at $46mn and G&A at $18mn. At that rate, they have cash for about 3 more quarters only.
AGEN is something of a perpetually “getting there” stock trading at the middle of its 52-week range. The Botensilimab molecule has promise, however confirmation of that promise is still months away. The problem with Agenus is, it has shown a lot of promise in 28 long years - and never delivered. Being a cautious investor with limited resources, I think I will watch this from the sidelines.
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Disclosure: I/we have no stock, option or similar derivative position in any of the companies mentioned, and no plans to initiate any such positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.