Stay at the forefront of the week’s champions and runners-up among publicly traded biotech companies and the reasons behind the ups or downs of their stock price fluctuations.
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Summit Therapeutics (SMMT) is living up to its name and then some with a cancer collaboration announced this week that could reach the stratosphere if all goes right. Summit has agreed to pay Chinese drug developer Akeso Biopharma (9926.HK) up to $5 billion—one of the largest collaboration deals of 2022—to develop and commercialize Akeso’s cancer candidate ivonescimab, starting first in non-small cell lung cancer (NSCLC).
The deal, announced Tuesday, would give Summit rights to the bispecific antibody it calls SMT112 in the U.S., Canada, Europe, and Japan—leaving Akeso with rights in China and Australia (where the antibody is called AK112), and the rest of the world. Summit said it would begin treating patients in its first clinical trial of ivonescimab by the second quarter of 2023.
The up to $5 billion deal consists of Summit paying Akeso $500 million upfront, and up to $4.5 billion tied to Akeso achieving regulatory and commercial milestones. Summit also agreed to pay Akeso low double-digit percentage royalties, and to appoint to its board Akeso’s Chairman and CEO, Michelle Xia, PhD.
Summit investors roared their approval of the collaboration by sending the company’s shares nearly tripling (up 194%) on Tuesday, rocketing to $2.31 from Monday’s close of $0.785. Summit continued its heady climb on Wednesday, zooming another 33% to $3.08. Akeso shares inched up 1% on Tuesday from HDK 30.85 ($3.96) to HKD 31.15 ($3.99), then soared 19% the following day, to HKD 37.00 ($4.75).
“Akeso remains one of our top picks under our China biotech coverage thanks to its innovation/platform, its combination strategies, and potential hit-the-ground-running launches with its commercial partners. We also expect more prospects from its pipeline as they land more global partners,” Christopher Lui, an equity analyst with Jefferies, said Tuesday in a research note.
Lui cited positive data presented by Akeso in June at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO) from an open-label Phase Ib/II trial (NCT04900363) showing ivonescimab monotherapy to be safe and well tolerated in advanced NSCLC regardless of histology. Gr3/4 treatment-related adverse events (TRAEs) was 13.5%, with no TRAEs leading to permanent treatment discontinuation.
Among 54 treatment-naive patients with a PD-L1 tumor proportion score (TPS) of at least 1% with at least 1 post-treatment tumor assessment, the overall response rate (ORR) was 50% and disease control rate (DCR) was 93%. Among the 50 treatment-naive patients receiving more than 10 mg/kg of AK112 q3wk, the ORR among patients with TPS of 1% or greater was 60.0%; (50% for TPS of 1% to 49%; 76.9% for TPS of 50% or greater).
Also at ASCO 2022, Akeso presented data that associated ivonescimab with an ORR of 68.4% in a Phase II study (NCT04736823) in patients with NSCLC who failed to show improvement after taking EGFR-TKIs earlier—as well as a median Progression-Free Survival (mPFS) duration of 8.2 months when the antibody was combined with the chemotherapy combination of pemetrexed and carboplatin, compared with 4.3 months in patients treated with the chemo combo alone, the current standard of care.
In a separate cohort, ivonescimab combined with docetaxel in patients who failed PD-(L)1 and chemotherapies showed mPFS of 6.6 months as compared to an historical mPFS of 4.5 months with docetaxel alone, a current standard of care regimen for these patients.
Earlier this year, Akeson won approval from China’s National Medical Products Administration to commercialize Kaitanni (cadonilimab), a combined PD-1 / CTLA-4 bispecific indicated for the treatment of relapsed or metastatic cervical cancer patients who progressed on or after platinum-based chemotherapy. Kaitanni is the first and so far only PD-1 bispecific authorized in China.
After phase III win, Prometheus bound for liftoff
In Greek mythology, Prometheus was sentenced to eternal torment by the chief Greek god Zeus for stealing fire and giving it to humankind.
This week, the drug developer named for that Titan god met a much happier fate. Shares of Prometheus Biosciences (RXDX) nearly tripled, surging 166% on Wednesday from $36.06 to $95.80, after the company announced it would advance its lead pipeline candidate PRA023 into Phase III studies for ulcerative colitis (UC) and Crohn’s disease (CD) in the coming year, based on positive efficacy and safety results in the Phase II ARTEMIS-UC trial (NCT04996797) and the Phase IIa APOLLO-CD trial (NCT05013905).
In ARTEMIS-UC, PRA023 met the primary endpoint of statistically significant clinical remission (per modified Mayo Score) vs. placebo, with 26.5% of the 68 treatment patients who completed Cohort 1, vs. 1.5% of the study’s 67 placebo patients. Also, 36.8% of patients on PRA023 reached the secondary endpoint of endoscopic improvement (Mayo endoscopy subscore of ≤ 1), versus 6% of placebo patients.
In APOLLO-CD, 26.0% of patients on PRA023 achieved endoscopic response (p=0.002 compared to 12% prespecified historical placebo rate), while 49.1% of patients on PRA023 achieved clinical remission (p<0.001 compared to 16% prespecified historical placebo rate).
APOLLO-CD was a 12-week open-label study that enrolled 55 patients with moderate-to-severely active CD with endoscopically active disease who had failed conventional or biologic therapy. ARTEMIS-UC was a 12-week, double-blind, placebo-controlled, randomized study designed to assess the efficacy and safety of PRA023 in patients with moderate-to-severely active UC who have failed conventional or advanced therapy.
“We are beyond enthusiastic with these study results and what they could mean for patients suffering from IBD,” declared Mark McKenna, Chairman and CEO of Prometheus Biosciences. “The performance of PRA023 in both UC and Crohn’s patients has surpassed our expectations.”
Among analysts sharing McKenna’s enthusiasm is Thomas J. Smith, Senior Managing Director, Immunology and Metabolism, and a senior research analyst with SVB Securities.
“Overall, we see these topline data as significantly de-risking for PRA023’s potential first-in-class/best-in-class profile, validating blockbuster opportunities in both UC and CD,” Smith wrote Wednesday in a research note. “In our view, the topline data appear compelling.”
Smith cited the strong results from ARTEMIS-UC, results from APOLLO-CD which he said suggested “strong proof-of-concept data indicative of viability in CD,” favorable safety and tolerability data, and “early signals that are strongly supportive of a biomarker-driven strategy.”
Analyst feedback hammers Gossamer
Gossamer Bio (GOSS) shares cratered 73% on Tuesday, from $9.29 to $2.36, then dropped another 8% on Wednesday to $2.16, based on negative analyst feedback on the company’s announcement of positive topline data from its Phase II TORREY trial (NCT04456998) assessing seralutinib in patients with pulmonary arterial hypertension (PAH).
Among results highlighted by Gossamer were pulmonary vascular resistance (PVR) data that favored seralutinib across all pre-specified patient sub-group analyses; an observed mean difference of 6.5 meters (21.3 feet) that favored seralutinib in the six-minute walking distance (6MWD) test; and a mean difference in PVR between the placebo and seralutinib arms of -96.1 dynes (p = 0.0310), equating with a placebo-corrected improvement of 14.3%.
Joseph P. Schwartz, Senior Managing Director, Rare Diseases, and a senior research analyst with SVB Securities, wrote in a research note that Gossamer’s 6MWD and PVR endpoints fell below Phase II placebo-adjusted data disclosed for Merck & Co.’s PAH candidate sotatercept, an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein (0.3 and 0.7mg/kg every 3 weeks) of 19%-32% PVR improvement and +21.4-29.4- meter 6MWD benefit. (Merck reported positive results in October from its Phase III STELLAR trial [NCT04576988], with data to be presented at an upcoming scientific conference.)
“We expect the street to be disappointed in these topline results,” Schwartz wrote of Gossamer’s announcement. “We note that the topline data also fell below our base case expectation for seralutinib vs. placebo to show a 20-30% PVR reduction and 15-20-meter 6MWD benefit.”
That may explain why Gossamer highlighted data from functional Class (FC) III PAH patients treated with seralutinib. The data showed a 21% reduction in PVR (p = 0.0427) and 37-meter (121.4 foot) improvement in 6MWD (p = 0.0476) compared with placebo patients. In patients with a baseline REVEAL 2.0 Risk Score of 6 or greater, seralutinib patients showed a 23% reduction in PVR (p = 0.0134) and 22-meter (72.2 foot) improvement in 6MWD (p = 0.2482) vs. placebo.
“Seralutinib significantly improved hemodynamic, biomarker, and right heart structural and functional measures in a heavily treated PAH patient population,” Faheem Hasnain, Gossamer’s co-founder, chairman, and CEO, said in a statement.
After Gossamer presented additional data on a conference call with analysts, Schwartz said the disappointment he expressed in the topline results “can be explained by an overall baseline criteria skew and randomization imbalance towards milder patients.
“We believe the subset analysis provided by GOSS should not be overlooked since if this can be modified in Phase III, seralutinib could still emerge with a highly compelling clinical profile,” Schwartz added.
Seralutinib is a dry powder inhalable tyrosine kinase inhibitor designed to treat PAH by triple-targeting platelet-derived growth factor alpha and beta (PDGFRα/β), colony stimulating factor 1 receptor (CSF1R), and tyrosine-protein kinase Kit (c-KIT).
Merck trial comparison, stock sales sink Mirati shares
Mirati Therapeutics (MRTX) stock plummeted 47% this week despite coming out with data that it insisted showed favorable results from the combination of its oral small-molecule inhibitor of KRASG12C adagrasib (MRTX849) and Merck & Co.’s immunotherapy blockbuster Keytruda® (pembrolizumab).
The combination was shown to demonstrate promising preliminary efficacy and favorable tolerability in patients with first-line advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation, according to data Mirati presented at the European Society for Medical Oncology Immuno-Oncology (ESMO IO) Congress 2022.
The data came from two clinical studies, the Phase II KRYSTAL-7 trial (NCT04613596) and a cohort of the Phase Ib KRYSTAL-1 trial (NCT03785249) evaluating the combo of adagrasib (400mg twice daily) and Keytruda in patients for the treatment of first-line NSCLC harboring a KRASG12C mutation across all PD-L1 subgroups.
More specifically, among the 53 patients who were clinically evaluable and received at least one on-study scan, adagrasib and Keytruda showed an objective response rate (ORR) of 49% (26 patients) across all PD-L1 subgroups—a sign of promising preliminary clinical activity, Mirati asserted. Six of the 26 occurred at a second on-study scan or later.
The 49% ORR result was “relatively modest,” according to Andrew Berens, MD, Senior Managing Director, Targeted Oncology and a senior research analyst with SVB Securities, though he kept the firm’s “Outperform” rating on Mirati stock. Berens wrote in a research note that the standard combination of Keytruda plus chemo resulted in an ORR of 48% in Merck’s KEYNOTE-189 clinical trial, which also showed an 11.2-month duration of response across PD-L1 expressing subgroups in the study.
“KRAS tumors tend to be more sensitive to CPI [checkpoint inhibitor treatment], suggesting a higher bar than seen in KEYNOTE-189, which was not limited to KRAS mutants,” Berens cautioned.
Berens added that Mirati’s abstract did not break out the efficacy results stratified by TPS scores or include duration of the responses, both of which he said will be critical in determining whether there is any advantage to substituting adagrasib for chemotherapy in first-line (1L) treatment. In KEYNOTE-189, the combination showed a ~61% ORR in TPS ≥ 50% patients, a ~48% ORR in TPS 1-49% patients, and a ~32% ORR in TPS <1% patients, which according to Berens “may serve as benchmarks for the different 1L populations.”
Investors responded to Mirati’s data announcement with a selloff that sent Mirati stock falling from $92.75 at the close of trading 49.59/92.75=Monday just before the announcement. Shares fell 23% on Tuesday to $71.52, then plunged another 31% to $49.59 on Wednesday, In addition to uncertainty over whether adagrasib could substitute for chemo, investors appeared to show frustration over two Mirati executives selling shares of the company’s stock recently. Chuck Baum, Mirati’s President, Founder, and Head of Research and Development, sold 69,028 shares on November 28, followed on December 5 by Chief Scientific Officer Jamie Christensen sold 1,726 shares.
Mirati also highlighted an ORR of 57% shown by four of seven evaluable patients enrolled in the KRYSTAL-1 Phase 1b cohort (with a median follow-up of 19.3 months). The four patients who responded maintained response for over nine months while two continued to receive treatment and remain in response beyond 18 months.
Mirati plans to advance adagrasib into a Phase III trial: “This data further underscores the potential of adagrasib as a well-tolerated treatment option for patients,” Baum said in a statement. “We look forward to progressing our clinical development in the first line setting with a goal of providing better options for patients with NSCLC harboring a KRASG12C mutation.”
The company is also planning to conduct a second Phase III in PD-L1-high patients with TPS scores of 50% or more, assessing the combination of adagrasib-Keytruda vs Keytruda monotherapy.
“Ultimately, we think the data will continue to fuel speculation on whether the KRASG12Cm inhibitor can successfully achieve a place in the 1L treatment paradigm commercially,” Berens added.
He estimated that adagrasib could generate peak sales in 1L of $1.7 billion, which would translate to $23 per share of Mirati’s future price.
Realignment misaligns MEI shares
MEI Pharma (MEIP) shares tumbled 33% on Tuesday, the first trading day after the company announced it would eliminate on staggered basis an initial 30% of its current workforce, as part of a realignment of its clinical development efforts sparked by the company’s decision to end development outside of Japan of zandelisib, a cancer-fighting candidate the company had been developing (and sharing related costs) with Kyowa Kirin.
In Japan, Kyowa Kirin will continue trials and efforts to gain approvals for zandelisib (formerly ME-401), an oral phosphatidylinositol 3-kinase (P13K) Delta inhibitor that has been in multiple ongoing trials assessing patients with B-cell malignancies.
Through the realignment, MEI plans to refocus its pipeline development efforts on its two most advanced candidates, the oral CDK9 inhibitor Voruciclib, being developed alone and in combination with standard therapies to treat blood cancers and solid tumors; and ME-344, a mitochondrial inhibitor being developed to fight solid tumors.
Investors responded to the job cuts and pipeline realignment with a selloff that sent MEI shares falling further into penny-stock territory, from 39 to 26 cents a share.
Last month, Jefferies analyst Chris Howerton, PhD, lowered the firm’s price target on MEI, from 50 to 40 cents a share, and maintained its “Hold” rating on the stock, citing FDA skittishness about granting further accelerated approvals to P13K treatments.
“We think FDA concerns with the safety of PI3Kδ inhibitors remain an obstacle to success,” Howerton wrote last month in a research note.
MEI and Kyowa Kirin had been pursuing an accelerated approval for zandelisib until March. That month, during a meeting with agency officials, the companies were told that they and other developers of P13K inhibitor candidates would have to conduct randomized trials to assess efficacy and safety of their treatments. “The agency discouraged a filing based on the Phase 2 TIDAL study data and emphasized that the companies continue efforts with the ongoing, randomized Phase 3 COASTAL study as planned.
MEI and Kyowa Kirin responded by holding off on earlier plans to file for approval of zandelisib based on TIDAL data. Accordingly, in line with the FDA’s recommendation, the companies do not plan to submit an FDA marketing application based on the single arm Phase 2 TIDAL study. Instead, the companies said they would carry out COASTAL, for which MEI said it had enough cash to complete trial enrollment in 2024.
