Although the placebo response proved better than expected in Chiasma Inc.'s phase III trial of Mycapssa (octreotide) capsules for acromegaly, "we believe that the response of the patients on Mycapssa is the clinically relevant indicator," said William Ludlam, the Waltham, Mass.-based firm's senior vice president of clinical development and medical affairs.
Wall Street agreed. Chiasma's stock (NASDAQ:CHMA) closed Tuesday at $7.86, up $1.66, or 26.8%, after trading as high as $9.25. Conducted over nine months in 56 patients under a special protocol assessment with the FDA, the study met its primary endpoint: 58% of the patients on octreotide capsules maintained their IGF-1 response compared to 19% of the patients on placebo (p=0.008). All secondary endpoints were met, too, with no new safety signals turning up. Mycapssa was designed to provide an oral somatostatin analogue (SSA) as an alternative to painful injections already on the market. The company plans to file an NDA application by the end of this year.
In the experiment, 78% of patients treated with Mycapssa maintained their growth hormone (GH) levels below 2.5 ng/mL at the end of the core study vs. 30% of patients treated with placebo (p=0.001). Median time to loss of response (IGF-1 >1 × upper limit of normal [ULN]) was not reached (>36 weeks) for patients treated with Mycapssa vs. 16 weeks for patients treated with placebo (p <0.001). Median time to loss of response (IGF-1 ≥ 1.3×ULN) was not reached (>36 weeks) for patients treated with octreotide capsules vs. 16 weeks for patients treated with placebo (p<0.001). Twenty-five percent of patients treated with octreotide capsules required rescue medication with injectable SSAs (octreotide long-acting release [Sandostatin, from Basel, Switzerland-based Novartis AG] or lanreotide depot [Somatuline, from Ipsen Pharma SA, of Paris) anytime throughout the study vs. 68% of patients treated with placebo (p=0.003).
In a prespecified exploratory endpoint, mean IGF-1 values across all patients treated with Mycapssa (including primary endpoint nonresponders per protocol), remained within normal limits (≤ 1 x ULN) up to the end of oral treatment. For purposes of the analysis, the end of oral treatment value consisted of the average of week 34 and week 36 values for all patients who completed the study and, for those patients who needed required rescue medication, it was their last observed value prior to the use of the rescue drugs.
Cantor Fitzgerald analyst Brandon Folkes was impressed by the GH control shown and asked on Chiasma's conference call with investors what that might mean commercially. CEO Raj Kannan said that, "although we had [GH] as a secondary endpoint, I think physicians will focus on the IGF-1, because that's the reason for GH to be positive, right? IGF-1 has become sort of a primary marker, and that's why we had that as a primary endpoint," which represents a "very relevant" reason for patients to switch from an injectable to Mycapssa.
Roth analyst Yasmeen Rahimi said market prospects look good. "We were not only impressed Mycapssa achieved its desired efficacy goal, which is in line with our survey to drive adoption, but also it came with a spot-clean safety profile, with only two dropouts (5%) across the 36 weeks," she noted in a report. In June, she said "investors question[ed] the adoption of Mycapssa among endocrinologists, and the response rate needed to switch patients from SSA injectables to oral Mycapssa." Her firm screened 40 specialists who voiced "strong appetite to switch patients (75%) to Mycapssa if responder rates (IGF<1 x ULN) fall within about 54%."
'More to be desired'?
Wainwright's Douglas Tsao was enthusiastic as well. "We think the 58% response rate is strong enough to support our expectations for robust commercial adoption, resulting in peak sales of $388 million globally (assuming both U.S. and European approval)." He also alluded to the fact that 90% of the patients treated with Mycapssa elected to continue in the open label extension (OLE) as another favorable sign.
Gary Patou, head of clinical development, said officials "haven't given any information about the OLE yet," other than the 90% piece of news, "which we believe is a very good indicator of patients voting with their feet, having a good experience on the drug. And this was very consistent with what we saw" in an earlier experiment.
Analyst Tsao said that "importantly, the rate of dropouts was meaningfully reduced from Mycapssa's prior phase III trial (CH-ACM-001)," where the rate was nearly 32% over 28 weeks with 10 patients dropping out due to gastrointestinal (GI) adverse events, a hitch corrected in Optimal. "We expect this was due to better understanding on appropriate dose titration as well as management of GI issues," he said. The capsules are designed using Chiasma's Transient Permeability Enhancer (TPE) technology, which allows GI absorption of the unmodified peptide into the bloodstream. The stomach tends to degrade protein drugs given by mouth; TPE protects the peptide and increases bioavailability. (See BioWorld, April 19, 2016.)
Another player in the oral acromegaly space is San Diego-based Crinetics Pharmaceuticals Inc., with CRN-00808, at the phase II stage in trials called Evolve and Edge. The compound establishes a new class of oral selective non-peptide somatostatin receptor type 2 (SST2)-biased agonists, Crinetics said. Leerink analyst Joseph Schwartz likes its odds, even with Chiasma marching faster toward market. He predicted Chiasma's latest progress would have "limited read-through and stock impact on Crinetics, since CRN-00808 has a differentiated target product profile," one that "does not require patients to trade off efficacy for the convenience."
He was right about the stock price, as shares of Crinetics (NASDAQ:CRNX) closed Tuesday at $23.11, down 60 cents. "Mycapssa leaves more to be desired," he said, suggesting Crinetics' therapy could "reach both the complete and partial responder patient base by reducing tachyphylaxis through higher SST2 receptor selectivity, while potentially minimizing receptor internalization" and thereby gain an advantage over the Ipsen, Novartis and Chiasma drugs.