Shares of companies that develop chimeric antigen receptor T-cell (CAR-T) therapies stayed mostly flat this week after the FDA announced it was assessing the need for new regulations addressing what it called the “serious risk” that patients treated with the cancer-fighting therapies could instead develop new T-cell malignancies.

Those new cancers could result in “serious outcomes, including hospitalization and death,” the FDA stated, while adding that “the overall benefits of these products [CAR-T therapies] continue to outweigh their potential risks for their approved uses.”

At issue are cases of T-cell malignancies, including CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR-T immunotherapies.

The FDA said it had received 19 reports of new blood cancers in patients receiving CAR-T treatments for various cancers in the six years since the first two such therapies were approved—Kymriah® (tisagenlecleucel), marketed by Novartis (NVS) and approved in August 2017; and Yescarta® (axicabtagene ciloleucel), approved four months later and marketed by the Kite Pharma subsidiary of Gilead Sciences (GILD).

Of the 19 reports cited by the agency, 12 were cases of T-cell lymphoma reported by patients using the FDA Adverse Events Reporting System (FAERS). Other cases came to the FDA’s attention through clinical trials.

The news was enough to send shares falling on Tuesday morning for some CAR-T drug developers—notably those with such treatments in their pipelines, or smaller biotechs. Among pipeline companies, Autolus Therapeutics (AUTL) shares took the biggest tumble, nosediving 35% from Monday’s close of $4.78 to $3.11 at 12 p.m., before finishing the day at $4.55, only a 5% single day drop. But shares skidded another 10% Wednesday, to $4.08, before partially rising 5% to $4.27 Thursday as of 11:35 a.m.

Faring better was Arcellx (ACLX), whose shares slid 8% from its Monday close of $53.21 to $49.01 at 12 p.m. before finishing Tuesday down 4% at $51.10. Arcellx lost another 1% Wednesday, before upticking 3% to $52.20 as of 11:35 a.m.

Among approved CAR-T therapy developers, Legend fell 7% from Monday’s close of $61.56 to $57.42 as of 12:30 p.m., before rising again to $59.99, a 3% one-day decline.

Giants hardly budge

Significantly, J&J and other biopharma giants with approved CAR-T treatments hardly budged:

  • BMS declined just 0.3% from $49.02 at Monday’s close to $48.85 at 3:30 p.m., finishing the day 1% higher at $48.92.
  • Gilead dipped 0.8% from $74.92 Monday to $74.30 at 1:30 p.m., before inching up 0.2% to finish at $74.51.
  • J&J also slid 0.3% from $151.28 to $150.88 at the start of trading Tuesday, then rallied to end the day up 0.5% at $151.63.
  • Novartis fell 1% from $97.74 to $96.67 at the start of Tuesday trading, but finished up 0.3% to an even $97.

All five makers of approved CAR-T therapies didn’t budge much Wednesday, closing anywhere from down 1% (Arcellx) to up 1% (Gilead).

Kymriah and Yescarta are two of six CAR-T cancer immunotherapies approved by the FDA. The other four are Abecma® (idecabtagene vicleucel), marketed by Bristol Myers Squibb (BMS; stock ticker BMY); Breyanzi® (lisocabtagene maraleucel), also marketed by BMS; Carvykti™ (ciltacabtagene autoleucel), marketed by Johnson & Johnson (JNJ)’s Janssen Biotech and Legend Biotech (LEGN); and Tecartus® (brexucabtagene autoleucel), marketed by Gilead.

$2.766 billion and growing

Revenues for the approved CAR-T treatments reached a combined $2.766 billion in the first nine months of this year, with most of them therapies growing significantly year-over-year.

During January-September 2023, Gilead generated the most in CAR-T sales, reporting $1.13 billion for its blockbuster Yescarta (up 37% from $823 million a year earlier) and another $272 million for Tecartus (up 25% from $217 million).

Next highest was BMS with $372 million for Abecma (up 41% from $263 million) and $263 million for Breyanzi (up 107% from $127 million), then Novartis with $388 million from Kymriah (down 2% from $397 million). Following closely is J&J’s $341 million from Carvykti, (more than quadruple, zooming 332% from $79 million—not counting Legend’s $152 million in Q3 net trade sales, plus a $131.2 million increase in collaboration revenue due to increased revenue from Carvykti sales).

Baird senior research analysts Brian P. Skorney and Jack K. Allen and colleagues said they expected only a limited impact on the commercial use of CAR-T therapies in later lines of treatment, given the desperation of patients and physicians in severe refractory B-cell malignancies, as well as the FDA’s affirmation of a favorable risk/benefit profile.

But the growth strategies for CAR-T therapies generally involve label expansion into earlier lines of treatment, according to Skorney and Allen—such as Yescarta’s effort to add an indication for second-line diffuse large B cell lymphoma (DLBCL).

“T-cell malignancies tend to be rapidly progressing cancers with few treatment options. Thus, we believe this update may impact the therapeutic index calculation for regulators and prescribers when it comes to earlier lines of treatment and less aggressive forms of B-cell malignancies (e.g., CLL, follicular lymphoma),” Skorney and Allen observed. “While this dynamic could limit the commercial potential of CAR-T products in earlier line indications, given the substantial number of unknowns here it is difficult to quantify the potential effect.”

“Substantial hurdle” for autoimmunity

They added that the potential for T-cell malignancy, a rare but highly fatal side effect, “is likely to present a substantial hurdle for expansion into autoimmune indications, where the expected tolerance for safety events is expected to be substantially diminished relative to oncology indications.”

That explains, according to the analysts, why immunology CAR-T cell therapy developer Cabaletta Bio (CABA) plummeted 27% on Tuesday, from $18.70 to $13.69. Since then, Cabaletta has risen 17%, to $13.88 on Wednesday and $16.05 on Thursday.

“Development focus may shift to increase attention on T-cell malignancy rates,” Skorney and Allen forecasted. “As a product of this investigation and any subsequent regulatory action, we expect that biotechs focused on the cell therapy space are going to heighten their focus on T-cell-related adverse events going forward. Although the mechanism behind the induced malignancies appears to be uncertain currently, we expect this side effect may become a larger focus for biotechs with commercialized cell therapies and those currently in the development stage.”

Of the 19 cases that sparked the FDA investigation, 12 were T-cell related malignancies. That number contrasts with the 46 total CAR-T related cases of acute myeloid leukemia (AML) and 60 of myelodysplastic syndrome (MDS) reported to FAERS, John Newman, PhD, an analyst with Canaccord Genuity, wrote Wednesday in one research note.

“Ultimately, we expect FDA to conclude that the risk of CAR-T cells becoming or causing T-cell cancers is low, and manageable, but we await the conclusion of FDA’s investigation,” Newman predicted in a second note to investors. “We suspect FDA will better quantify the risk of serious outcomes after T-cell cancers following CAR-T therapy, and then update product labels accordingly.

He cited the fact all CAR-T therapies already have a class warning in place for the potential of developing secondary malignancies.

“Importantly, if FDA has serious concerns, they could have halted ongoing CAR-T trials, and/or halted treatment of patients with approved CAR-Ts,” Newman added. “The fact that they did neither suggests overall risk is manageable, in our view.

More than half of the 12 T-cell malignancy cases (seven) were from patients treated with Kymriah. Another three were treated with Yescarta, and one each with Breyanzi and Carvykti. No cases arose from Abecma and Tecartus patients.

“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA advised.

However, Newman cautioned: “Importantly, we do not know the total number of Carvykti and Abecma patients treated. We also do not have T-cell malignancy data on any CAR-T products still in clinical studies.”

Leaders & laggards

  • Altamira Therapeutics (CYTO) shares yo-yoed this week after the company said it was notified by Nasdaq that it had regained compliance with the exchange’s minimum stockholders’ equity requirement. Shares nearly tripled, leaping 280% on Wednesday from 23 to 64.5 cents, only to plummet 39% Thursday to 39 cents on apparent profit-taking. The company improved its equity position in recent months by selling common shares, partially amortizing convertible debt, and spinning off a 51% stake in its subsidiary Altamira Medica in order to reposition Altamira as an RNA delivery technology company. Medica’s key asset is Bentrio®,a drug-free over-the-counter nasal spray designed to treat allergic rhinitis.
  • Biodexa Pharmaceuticals (BDRX) shares nearly doubled, rocketing 91% Monday from $2.67 to $5.11 after the company agreed to assume an exclusive worldwide license to develop and commercialize tolimidone for type 1 diabetes. Biodexa will be assigned the rights of Adhera Therapeutics (ATRX) under an exclusive, worldwide, sub-licensable license from Melior Pharmaceuticals to develop, manufacture, commercialize, or otherwise exploit tolimidone. Tolimidone is a selective activator of the enzyme lyn kinase which increases phosphorylation of insulin substrate -1, thus amplifying the signalling cascade initiated by the binding of insulin to its receptor. Tolimidone was originally discovered by Pfizer, which developed the drug as a treatment for gastric ulcers until it failed a Phase II trial due to lack of efficacy.
  • BioVie (BIVI) shares plunged 61%, from $4.99 to $1.96, on Wednesday after the company acknowledged that mild-to-moderate Alzheimer’s Disease (AD) candidate NL3107 missed its primary efficacy endpoint in a Phase III clinical trial (NCT04669028) due to exclusion of data from patients at 15 of the study’s 39 sites that made “significant” deviations from protocol and Good Clinical Practice. Of 439 enrolled patients, 81 patients remained in its modified intent to treat population, 57 of whom were in the per-protocol population which included those who completed the trial and were verified to take NL3107 from pharmacokinetic (PK) data. BioVie said data from evaluable patients showed NE3107 outperforming placebo equal to or greater than the benefit shown by approved AD monoclonal antibodies. NE3107-treated patients also enjoyed a 4.66-year advantage in age deceleration vs. placebo, BioVie said.
  • RedHill Biopharma (RDHL) shares zoomed more than nine-fold (911%) over three trading days, from $0.3155 to an even $1 on Monday, then climbing to $2.28 on Tuesday and $2.88 on Wednesday. The surge followed the company announcing that the FDA granted it five years’ market exclusivity for Talicia (omeprazole magnesium, amoxicillin and rifabutin) under the Generating Antibiotic Incentives Now (GAIN) Act Qualified Infectious Disease Product (QIDP) designation, on top of three years’ exclusivity previously granted for the approval of Talicia. The FDA recently approved a supplemental NDA for Talicia, allowing a change to a more flexible three times daily (at least four hours apart with food) dosing regimen, which the company says will enable patients to follow a breakfast, lunch and dinner dosing routine that may support increased patient adherence and enhance the potential for successful H. pylori eradication.
  • Soligenix (SNGX) shares more than doubled, soaring 133% on Thursday, from 42 cents to 98 cents, after announcing that the FDA had cleared the IND application for a Phase 2a clinical trial entitled, “Pilot Study of SGX945 (Dusquetide) in the Treatment of Aphthous Ulcers in Behçet’s Disease.” The trial is an open-label study designed to evaluate the safety and efficacy of SGX945 (dusquetide) and is expected to begin patient enrollment in the second half of 2024. The study will enroll approximately 25 patients age 18 years or older with mild to moderate Behçet’s disease active oral and/or genital ulcers, Soligenix said.

Alex Philippidis is Senior Business Edigtor of GEN.

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