BioNTech (BNTX) recently took a significant step toward life beyond COVID-19 when it presented some promising data during the recent European Society for Medical Oncology (ESMO) Congress 2022 held in Paris.
Prof. Andreas Mackensen, MD, of University Hospital Erlangen, Germany, presented positive follow-up data during ESMO’s Investigational Immunotherapy Proffered Paper Session from BioNTech’s ongoing Phase I/II trial (NCT04503278; 2019-004323-20) assessing its wholly-owned novel chimeric antigen receptor T-cell therapy (CAR-T) candidate BNT211 in patients with relapsed or refractory advanced solid tumors.
The 21 evaluable patients (of 22 patients overall) showed a best overall response rate (ORR) of 33% and a disease control rate (DCR) of 67% with one complete response, six partial responses and seven patients with stable disease, BioNTech reported.
“While small patient numbers and early stage of data prevent definitive conclusions, our KOL [key opinion leader] is encouraged by the profile and is hopeful that the data may reflect positively on the potential for cell therapies in solid tumors,” Bill Maughan, PhD, a director and Senior Analyst-Biotechnology with Canaccord Genuity, wrote Tuesday in a research note based on opinions from an unnamed “oncology KOL.”
“Further, the data add excitement to the potential of cancer vaccines, which she and her colleagues are eager to study in additional clinical trials,” Maughan added.
That excitement did not appear to be shared by investors. Between September 9 when the BNT211 data was announced and yesterday, BioNTech shares slid 6.5%, from $150.91 to $141.05, though shares rose 4% yesterday, to $146.55, after Pfizer said it dosed the first patients in a Phase III study of an RNA-based flu vaccine on which BioNTech stands to collect royalties upon commercialization.
One likely reason why investors shied away: The 33% ORR and 67% DCR reported for BNT211 marked a drop from the 43% ORR and 86% disease control rate reported by BioNTech for the vaccine candidate back in April, based on 14 evaluable patients in the trial.
BNT211’s therapeutic approach combines two of BioNTech’s platforms—an autologous CAR-T cell therapy targeting the oncofetal antigen Claudin-6 (CLDN6) with a CLDN6-encoding CAR-T cell amplifying RNA vaccine (CARVac).
Patients received CLDN6 CAR-T cells at two dose levels. Seven patients received the smaller dose of 1×107 CAR-T cells, including one patient who received a CAR-T dose below dose level 1. The other 15 patients received the larger dose of 1×108 CAR-T cells, alone or combined with CARVac.
Particularly encouraging, according to BioNTech, were the clinical responses were seen in patients with testicular cancer treated with the larger dose: One complete response, three partial responses and two stable diseases were seen, representing an ORR of 57% and a DCR of 85%.
Antitumor activity was higher at the higher dose of CAR-T cells and when combined with the mRNA vaccine. All 22 patients showed robust, dose-dependent CAR-T cell expansion after infusion with cell frequencies close to 109 total counts in the larger dose, the company said.
Five of 10 patients in the CARVac combination group showed a partial response compared to two of nine patients in the monotherapy cohort (CAR-T cell treatment only—a result that excluded two patients who were treated without lymphodepletion.
In June, BNT211 received the European Medicines Agency (EMA)’s Priority Medicines (PRIME) designation for the third- or later-line treatment of testicular germ cell tumors.
“This new dataset further supports the encouraging results we have seen for BNT211 to date,” said Prof. Özlem Türeci, MD, Co-Founder and chief medical officer at BioNTech. “Together with the recently granted PRIME designation for BNT211 in testicular cancer it also reinforces our strategy to combine two of our key technology platforms in hard-to-treat tumor indications.”
Tumor indications included testicular cancer (13 patients), ovarian cancer (four), endometrial cancer, fallopian tube cancer, sarcoma, gastric cancer (one patient each) and one patient with a tumor of unknown primary origin. At the cut-off date (August 16 for efficacy, June 15 for safety), data showed the long-term persistence of CAR-T cells observed in some patients for more than 100 days, and in one patient for 200 days.
Adverse events, including cytokine release syndromes (CRS) and dose limiting toxicities were manageable. One transient occurrence of neurotoxicity grade 1 and one grade 3 CRS were observed that quickly resolved.
BioNTech reasons that the combination of engineered T cells and mRNA vaccines in one treatment regimen can stimulate and expand T cells. “This could enable us to develop truly powerful precision immunotherapies,” Türeci stated in June.
Akero Therapeutics (AKRO)
Akero shares more than doubled on Tuesday, rocketing 137% from $12.27 to $29.05 after the company released positive top-line data from its Phase IIb HARMONY trial (NCT04767529) showing that both dosages of its lead product candidate efruxifermin (EFX) met the study’s primary endpoint by resulting in a ≥1 stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH). The 50 mg dosage showed a 41% improvement, compared with 39% for the 28 mg dosage—double the 20% rate shown by placebo.
Akero also said both dosages of EFX met two key secondary endpoints. showed NASH resolution without worsening of fibrosis, ranging from three times the 15% placebo rate for the 28 mg dosage (47%), to about five times for the 50 mg dosage (76%). Also, EFX showed combined fibrosis improvement and resolution of NASH at six times the 5% placebo rate for the 28 mg dosage (29%), and eight times for the 50 mg dosage (41%).
“We believe today’s results from the HARMONY study are an important milestone not only for Akero but for the entire NASH community,” Andrew Cheng, MD, PhD, Akero’s President and CEO, said in a statement. “We believe the data are very compelling and show EFX’s potential to meet the critical, global unmet need for patients by intervening across stages of disease progression, potentially addressing both early-stage metabolic drivers and later-stage inflammation and fibrosis.”
The company is discussing plans for a late-stage study of EFX projected to start next year with U.S. and European regulators, Akero chief development officer Catriona (Kitty) Yale told analysts Tuesday during a conference call.
Akero is one of several companies developing NASH treatments, along with 89bio, Intercept Pharmaceuticals, Inventiva, Madrigal Pharmaceuticals, and Novo Nordisk. NASH represents a potential multi-billion-dollar opportunity for drug developers, Brian Abrahams, a managing director and Head of Biotechnology Equity Research with RBC Capital Markets, estimated in an investor note reported by Investor’s Business Daily.
Akero bookended Tuesday’s morning announcement of EFX’s good news by disclosing at the end of the day that it had commenced a $175 million underwritten public offering of its common stock. The company is granting underwriters a 30-day option to buy up to an additional $26.25 million of shares at the public offering price, minus underwriting discounts and commissions.
J.P. Morgan, Morgan Stanley and Jefferies are acting as joint book-running managers for the proposed offering. Canaccord Genuity is acting as lead manager and H.C. Wainwright is acting as co-manager for the proposed offering.
Akouos (AKUS)
Akouos shares climbed 37% earlier this week, paced by a 28% jump on Tuesday from $3.50 to $4.48 after the company announced that it received FDA clearance for its Investigational New Drug (IND) application to begin a Phase I/II, first in human, pediatric clinical trial of its AK-OTOF—the first time the agency has cleared an adeno-associated virus (AAV) vector gene therapy designed to treat an inner ear condition.
AK-OTOF is a dual adeno-associated viral (AAV) vector-based gene therapy designed to treat patients with OTOF-mediated hearing loss by delivering transgenes encoding OTOF to the inner hair cells (IHCs) of the cochlea. A one-time, unilateral intracochlear administration of AK-OTOF is intended to result in the expression of normal full-length functional otoferlin protein in the IHCs, which has the potential to lead to recovery of auditory function.
The Phase I/II trial is designed to evaluate the safety and tolerability of escalating doses of AK-OTOF administered unilaterally to trial participants with OTOF-mediated hearing loss. The study is also designed to assess efficacy through clinical measures such as the auditory brainstem response (ABR).
“We expect this to be the first clinical trial for a genetic inner ear condition, the first in which an AAV gene therapy is administered to the inner ear, and the first for any inner ear condition to begin in a pediatric population,” said Manny Simons, PhD, MBA, Akouos’ co-founder, President, and CEO.
Jack K. Allen, CFA, Senior Research Analyst with Baird, is watching closely AK-OTOF as well as potential head-on competitor DB-OTO, the dual-vector AAV lead gene therapy candidate of Decibel Therapeutics (DBTX). DB-OTO is designed to restore hearing to individuals with profound, congenital hearing loss caused by mutations of the otoferlin gene.
“While we believe there are a number of fundamental differences in the design and administration of Decibel’s and Akouos’ candidates, moving forward we plan to monitor both programs closely as we anticipate initial data from either program is likely to have competitive readthroughs,” Allen wrote August 31 in a research note.
Altimmune (ALT)
Altimmune shares started Wednesday by plunging 57% before partially recovering, finishing the day down 27%. The declines occurred despite the company reporting positive topline results from its 12-week Phase Ib trial (NCT05006885) of pemvidutide in subjects with non-alcoholic fatty liver disease (NAFLD).
Why the disconnect? Possible reasons emerged among investors discussing the stock on Stocktwits. One investor, “AskmeifIcare,” cited research notes by Liisa Bayko, a managing director and research analyst with Evercore ISI, and Jonathan Wolleben, equity research analyst, biotechnology and biopharmaceuticals with JMP Securities.
Bayko expressed disappointment with the approximately 5% weight loss in 12 weeks shown in the trial, though the percentage was above that recorded in a study by Novo Nordisk’s marketed drug Rybelsus® (semaglutide). Wolleben said the percentage was below that of an earlier Phase I trial of pemvidutide, and below the expectations of many investors. Both analysts rate Altimmune shares “Outperform,” with price targets of $14 a share (Bayko) and $28 a share (Wolleben).
However, Jefferies analyst Roger Song, MA, CFA, noted that the 5% weight loss of pemvidutide was in line with historical results ranging from ~4-6% for two marketed once-weekly drugs: Novo Nordisk’s obesity treatment Wegovy® (semaglutide) in studies for NASH and obesity, and Eli Lilly’s Mounjaro™ (tirzepatide) in obesity.
Song said the high percentages of Hispanic patients in each treatment arm—figures the company quietly disclosed within an investor presentation of study results—”could have impacted the results”–20 of 23 patients dosed with 1.2 mg (87%); 19 of 23 dosed with 1.8 mg (82.6%); 18 of 24 dosed with 2.4 mg (75%); and 14 of 24 placebo patients (58.3%).
“While there are not many precedents or mechanistic reasons suggesting the correlation, we did find one data point supporting that Hispanic pts [patients] might do worse in weight loss vs. non-Hispanic in response to GLP-1 treatment,” Song wrote today in a research note. “We will wait for Ph2 obesity results to better assess pemvi’s weight loss efficacy.”
Song added: “It’s too early to write off pemvi’s potential best-in-class weight loss efficacy, considering: 1) this is an NAFLD vs. obesity study, with a few key differences (higher/lower baseline LFC [liver fat content] /ALT [alanine aminotransferase]) vs. other NAFLD/NASH studies; 2) sample size is still relatively small with 12W [12-week] treatment period; 3) Co has two more data readouts from a well-designed Ph2 obesity study (with typical pt baseline vs. other obesity trials) with longer term (24/48W) treatment.”
Pemvidutide—a peptide-based GLP-1/glucagon dual receptor agonist being developed to treat obesity and nonalcoholic steatohepatitis (NASH)—met the study’s primary efficacy endpoint of statistically significant reduction in liver fat content from baseline compared to placebo in all three treatment groups, based on doses of 1.2 mg, 1.8 mg, and 2.4 mg, administered weekly for 12 weeks.
At the 1.8 mg dose (with and without diabetes), pemvidutide achieved a mean reduction of liver fat content of 68.5%, with 94.4% of participants achieving a 30% reduction in liver fat, 72.2% achieving a 50% reduction in liver fat, and 55.6% achieving normalization of liver fat (5% or less). Mean serum alanine aminotransferase (ALT) levels declined in all participants. In subjects with baseline serum ALT above 30 IU/L, levels declined more than 17 IU/L at all dose levels and 27.0 IU/L in the 2.4 mg dose cohort.
Pemvidutide also met the study’s key secondary efficacy endpoint of statistically significant weight loss from baseline at 12 weeks of treatment. Altimmune said mean weight losses of 4.9% (placebo-adjusted 4.7%) in subjects without diabetes and 4.4% in subjects with diabetes (placebo-adjusted 3.9%) were achieved at the 1.8 and 2.4 mg doses, respectively.
“We are pleased with the results of this trial, including the extent of liver fat and serum ALT reductions. Weight loss was within our target range, and good tolerability was observed without the need for dose titration,” stated Vipin K. Garg, PhD, Altimmune’s president and CEO.
Rubius Therapeutics (RUBY)
Rubius shares tumbled 31%, from $1.07 to 74 cents, between Tuesday and yesterday, after the company announced a cost-cutting restructuring that included eliminating 75% of its workforce—about 160 of the 213 employees the company reported as of July 31. The job cuts are primarily focused on clinical development of its two lead candidates, as well as manufacturing and general and administrative positions.
“This workforce reduction is expected to be substantially completed in November 2022,” Rubius stated in a regulatory filing. “Additionally, the Company is exploring the sale of its manufacturing facility in Smithfield, Rhode Island.”
Rubius said it could not determine how much it would record in charges related to the job cuts, but would do so through an amended filing or a quarterly report.
The cell therapy company focuses on developing Red Cell Therapeutics™ designed to treat cancer and autoimmune diseases. Rubus said it was restructuring in order to advance a next-generation red blood cell-based cell conjugation platform that according to President and CEO Pablo J. Cagnoni, MD, “has the potential for substantive improvements over our existing platform.”
As a result, Rubius is halting trials and development of its two lead candidates. One is its lead oncology program RTX-240, an allogeneic, off-the-shelf cell therapy engineered to simultaneously present hundreds of thousands of copies of 4-1BB ligand (4-1BBL) and IL-15TP (trans-presentation of IL-15 on IL-15Rα) in their native forms. The other candidate being jettisoned is RTX-224, an allogeneic cell therapy engineered to express hundreds of thousands of copies of 4-1BBL and interleukin-12 (IL-12) on the cell surface.
“Continued investment in our two current clinical candidates is no longer justified,” Cagnoni declared.
He said the new platform held potential for greater efficacy and enhanced versatility, while maintaining a favorable tolerability profile.
Rubius said its restructuring will extend its cash runway from mid-2023 to the end of next year.