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The last couple of years have seen a number of competing oral SERDs lose out in trials. The list includes big name pharma and their major molecule candidates, Sanofi’s (SNY) amcenestrant and Roche’s (OTCQX:RHHBY) (OTCQX:RHHBF) giredestrant. However, there were some major successes as well, with Menarini’s elacestrant gaining FDA approval early last year, and AstraZeneca’s (AZN) camizestrant also doing well in a phase 2 trial. Olema (NASDAQ:OLMA) sits squarely in the middle of this melee, as the only small biotech with a fighting chance at winning in the oral SERD race.
That, however, became open to debate late last year after the company posted interim results from its Phase 1b/2 clinical studies for its lead product candidate palazestrant (OP-1250) in breast cancer in combination with CDK4/6 inhibitors ribociclib and palbociclib. According to the company, data showed “no significant drug-drug interaction, no dose-limiting toxicities and a tolerability profile consistent with the FDA-approved labels of ribociclib or palbociclib plus an endocrine therapy.” CBR rate, which is defined as the combination of Complete Response, Partial Response and Stable Disease, and demonstrates clinical efficacy, was as follows:
The clinical benefit rate was 46% in all patients and 60% in patients with an ESR1 mutation at baseline. In patients naïve to prior CDK4/6 inhibitor treatment, the CBR was 71%.
Now, compare that to the PALOMA-3 trial with palbociclib and another (non-oral) SERD:
In Asians, the CBR was 70% (95% CI, 59% to 80%) with palbociclib plus fulvestrant and 52% (95% CI, 33% to 70%) with placebo plus fulvestrant (odds ratio, 2.216; 95% CI, 0.85 to 5.7; Table 2). In non-Asians, the CBR was 66% (95% CI, 60% to 71%) and 37% (95% CI, 29% to 46%) in the palbociclib and placebo arms, respectively (odds ratio, 3.234; 95% CI, 2.1 to 5.0; P < .001).
Now, these were patients “whose cancer had relapsed or progressed (on the basis of histologic or cytologic confirmation of recurrent local or distant disease progression) during or within 12 months of completing adjuvant endocrine therapy or while on or within 1 month from prior endocrine therapy for advanced breast cancer or MBC. One previous line of chemotherapy for advanced or metastatic disease was allowed.”
There are certain important contrasts between this trial and Olema’s trial. For one thing, Olema’s trial was not randomized. That makes a lot of difference. Indeed, Olema’s drug arm only CBR was less than the CBR seen in the PALOMA-3 control arm with placebo and fulvestrant in Asians. Thus, it is impossible to draw direct conclusions. Secondly, the subgroups were very different. PALOMA-3 did not have treatment-naive patients, while in Olema, there was a nice 71% CBR in patients naive to prior CDK4/6 inhibitors. Importantly, fulvestrant was administered intramuscularly, while palazestrant is delivered orally. These are important differences that preclude a direct comparison.
Now take elacestrant, Menarini’s recently approved oral SERD. Elacestrant was approved specifically for patients with an ESR1 mutation, which drives disease resistance and occurs in about 40% of ER+, HER2- advanced or metastatic breast cancers patients. The data came from the Phase 3 EMERALD trial, which “demonstrated statistically significant progression-free survival (PFS) with elacestrant vs. SOC endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane), meeting both primary endpoints in all patients and in those patients whose tumors harbor ESR1 mutations.” Among the differences with Olema’s trial is that while EMERALD trial was for elacestrant monotherapy, like palazestrant’s trial cited here, it was a randomized trial. Thus, there are too many differences to directly compare results across these trials. Just having a SERD in the mix does not help.
However, Olema has made a number of comparisons and/or drawn conclusions from trial data of rival drugs. For example, improved upper GI tolerability with elacestrant capsules versus elacestrant tablets has been cited as an indication of palazestrant’s potential safety profile. Again, Olema compared palazestrant’s data with SABCS 2021 EMERALD trial data of elacestrant. Here’s that data. However, there are too many differences to directly compare these trials, and any effort to do so obfuscates the problem.
Olema’s stock has recovered after the data drop last month, showing that the market isn’t entirely unconvinced about the data, and is hoping for more clarity as studies progress, specifically the OPERA-01 pivotal Phase 3 monotherapy clinical trial, which has begun enrolling patients.
Financials
OLMA has a market cap of $766mn and a cash balance of $277mn. GAAP research and development (R&D) expenses were $19.5 million for the quarter ended September 30, 2023, Non-GAAP R&D expenses were $16.7 million, GAAP general and administrative (G&A) expenses were $3.9 million for the quarter ended September 30, 2023, while Non-GAAP G&A expenses were $2.6 million. At that rate, they have a cash runway of 10-12 quarters. Their G&A expenses are impressively low, assisted, no doubt, by the 25% workforce cut they undertook early in 2023.
Bottomline
Olema is at an interesting place right now. If I was a shareholder who bought a little below current prices, I would hold on for more data. However, if I was a buyer at much lower prices, I would definitely take profits. The data they have may have confused the market because a proper cross trial comparison, while very much needed, is not possible given the many differences. However, the trial, per se, is not so bad that we have to give up on the only small cap biopharma still left with an oral SERD.
