Kyverna Therapeutics has unveiled the full results from its registrational trial of miv-cel in stiff person syndrome (SPS), providing a comprehensive look at what could become the first-ever CAR-T therapy approved for an autoimmune disease.
The detailed analysis at the American Academy of Neurology (AAN) annual meeting demonstrated a clean sweep of positive results across all primary, secondary and exploratory endpoints. The trial performance underscores what Kyverna CEO Warner Biddle calls the “transformative impact” of miv-cel in a patient population with no FDA-approved treatment options, he told Fierce in an interview.
For the first time, a treatment has managed to improve clinical symptoms and reverse the course of SPS, made possible through delivering a deep immune reset, results from the phase 2 KYSA-8 trial show.
The full results should mitigate concerns regarding potential FDA roadblocks—at least from a clinical data perspective—at a time when the agency’s regulatory standards for rare disease therapies have become increasingly tough to decipher.
The comprehensive dataset “strengthens our clinical file that we will be submitting to the FDA,” Biddle told Fierce. “Given the productive dialogue and discussions we’re having with the FDA, we anticipate to file for full approval.”
As Kyverna previously announced in December, miv-cel delivered a 46% improvement compared with baseline on the trial’s primary endpoint, a timed 25-foot walk (T25FW) test at week 16, among 26 patients. And 81% of patients enjoyed a “clinically meaningful” improvement, defined as at least a 20% reduction from baseline.
Newly published detailed results now also show that of the 12 patients who required a walking aid at baseline, eight (67%) no longer needed assistance at week 16.
At the last follow-up, all 26 patients in KYSA-8 were able to discontinue all immunomodulatory or immunosuppressant therapies for SPS.
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For secondary endpoints, miv-cel achieved significant improvements across several measurements of disability, mobility, stiffness and hypersensitivity.
On the modified Rankin Scale (mRS), a 7-point clinician-reported scale used to measure the degree of disability, patients who received miv-cel got better by an average of 0.8 points.
On the 10-point, clinician-administered Hauser Ambulation Index, which is similar but slightly different from T25FW, miv-cel helped patients improve by an average of 1.6 points.
On two SPS-specific measurements, the Distribution of Stiffness Index (DSI) and the Heightened Sensitivity Scale (HSS), investigators recorded mean improvements of 1.5 points and 3.2 points, respectively.
As the study’s lead investigator, Amanda Piquet, M.D., from the University of Colorado, summarized during a press conference, the results are “truly remarkable.”
But how long miv-cel’s effects may last remains a lingering question, and one that’s particularly important because CAR-T therapies are typically meant to be given just once.
“Obviously, this is something that needs ongoing observation,” Piquet said. “But there’s early biomarker data looking at that immune reset. And I think that’s just really exciting that this therapy has the potential for that once-and-done.”
Miv-cel, full name mivocabtagene autoleucel, reprograms a patient’s T cells to recognize and destroy CD19-positive B cells, which are responsible for producing autoantibodies, allowing for a reset of the immune system. In SPS, which is estimated to affect about 1 to 2 people per million, autoantibodies block the glutamic acid decarboxylase (GAD) enzyme, which helps make the GABA neurotransmitter.
Besides B-cell depletion, KYSA-8 investigators also saw significant reductions in levels of GAD65 autoantibodies, consistent with miv-cel’s mechanism of action.
Even at just 16 weeks after treatment, the “magnitude and consistency of functional improvement observed is unprecedented,” Piquet said. As for Kyverna CEO Biddle, he suggested the findings “will be meaningful for the FDA as well.”
In another positive sign that miv-cel’s effect could be long-lasting, the first few patients who got miv-cel more than two years ago through a compassionate use program remain “steady with a very positive clinical response [and] reversal of disease symptoms, while also removing the background immunosuppressants and treatments” that they had been taking, according to Biddle.
Miv-cel also showed what Piquet called a “manageable” safety profile in KYSA-8. On cytokine release syndrome, which is common among CAR-T therapies, only grade 1 or 2 events were recorded. And for ICANS, a neurotoxicity that’s shared across the modality, only three (12%) grade 1 cases were reported.
There were four (15%) cases of grade 3 or 4 neutropenia, a very frequent issue with both the lymphodepletion required to prepare the body for CAR-T treatment and the cell therapies themselves. The cases were manageable using usual standards of care, Biddle said.
Potential FDA uncertainty?
Perhaps the one remaining uncertainty for miv-cel lies with the FDA—specifically, whether the agency will accept results from an open-label study with no control arm as sufficient evidence. The question carries new importance after the agency unexpectedly rejected uniQure’s plan of leveraging an external control cohort to support an application of its Huntington’s gene therapy candidate. While uniQure said it was caught off guard by the FDA’s alleged about-face, a senior FDA official said the agency has always asked for randomized clinical trials.
The FDA has never asked Kyverna to run a randomized trial for miv-cel in SPS, Biddle confirmed to Fierce.
“This is a rare disease with no approved therapies, and I think the FDA is very well aware of that, [and] very well aware of how transformative this data is as well,” Biddle said. “And there’s a sense of urgency, I think, on behalf of everybody, to get this to patients as quickly as possible.”
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At AAN, Kyverna also presented a separate natural history analysis based on data from two major SPS treatment sites—the University of Colorado where Piquet works and the Johns Hopkins University Stiff Person Syndrome Center. The natural history data put miv-cel’s treatment effect in context, Biddle said.
The analysis found that 70% of patients experienced T25FW improvements of less than 20% over a 10-year period despite current off-label treatment options. Simultaneously, walking aid use increased by 73% by the end of the analysis.
“The headline here is that patients at best remain flat, but the natural prognosis for these patients is that they get worse over time,” Biddle said.
“It’s very clear that this is a progressive neurologic disease and patients don’t respond” to off-label therapies as well as they did with miv-cel, Piquet said.
Myasthenia gravis update
As the SPS data appear poised to crown miv-cel as the first autoimmune CAR-T to reach the market, Kyverna is also making progress on other autoimmune conditions.
Building on a previous positive interim analysis of six patients, Kyverna at AAN confirmed a 100% response rate for miv-cel in generalized myasthenia gravis (gMG). The figure comes from a follow-up analysis of the phase 2 portion of the phase 2/3 KYSA-6 trial, with one more patient enrolled this time.
Patients were considered responders if they achieved at least a 3-point reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, which are the co-primary endpoints of the ongoing registrational portion of the trial.
The update showed deepening of responses, as the seven patients with moderate to severe gMG achieved average reductions from baseline of 8.5 and 11.3 points in MG-ADL and QMG at week 24, respectively.
Deep responses were sustained for up to year among the three patients who were followed that long, according to the results.
All seven patients achieved a clinically meaningful response, defined as a mean reduction of 16 points in the Myasthenia Gravis Composite (MGC) at 24 weeks. And all patients were free of immunotherapies through week 24. As Kyverna previously disclosed during the interim readout, one patient restarted immunosuppressants at week 33 out of their own decision rather than because of an MG flare, William Blair analysts pointed out in an April 20 note.
“These data continue to give us confidence that the phase 3 study that we’re now enrolling for myasthenia gravis will be a positive trial,” Biddle said.
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If successful, miv-cel could offer a very unique approach compared with other gMG treatments, such as complement inhibitors, which are used on top of other therapies.
In the study, miv-cel again showed a “very strong safety profile that makes it very amenable” to treating autoimmune diseases, the Kyverna chief executive said. The drug showed only low-grade CRS and no ICANS. Two patients’ transient high-grade neutropenia were fully resolved.
Miv-cel’s mechanism of depleting B cells suggests it may be useful across multiple B cell-mediated autoimmune diseases. In a recent study published in the journal Med, a team in Germany described successfully treating three autoimmune diseases in one patient with Miltenyi Biomedicine’s investigational CD19 CAR-T, zorpocabtagene-autoleucel (zorpo-cel).
Kyverna is simultaneously evaluating miv-cel in multiple sclerosis, lupus nephritis and systemic sclerosis.
“We’ll provide more updates on the next indications that we’re pursuing as a company, but this focus on neuroimmunology allows us to move quickly [and] bring this to patients with high unmet need,” Biddle said. “The synergies across these different indications makes it a very efficient way for us as a company to bring these therapies to market.”
