Next-Gen CAR T & Novel SMA Drug Among New Entrants On EMA’s PRIME
Rare Pediatric Disease Drug & Multiple Myeloma Therapy Also Make The Grade
Executive Summary
Autolus, Scholar Rock, Rocket and Pfizer have managed to convince the European Medicines Agency that their investigational treatments merit a place on the regulator’s priory medicines scheme.
AUT01 (obecabtagene autoleucel), a next-generation CAR T-cell therapy that Autolus Therapeutics is developing to treat relapsed/refractory lymphocytic leukemia (ALL), has secured a place on the European Medicines Agency’s PRIME (priority medicines) scheme.
AUT01 is an investigational CD19 CAR T-cell therapy that Autolus claims could overcome the limitations in clinical activity and safety compared with current CD19 CAR T-cell therapies. It recently showed promise in a Phase I clinical trial.
AUT01 was among four investigational drugs that recently won a place on PRIME, a scheme designed to help drug developers get promising medicines for unmet medical needs to patients faster.
Also accepted on the scheme was apitegromab (SRK-015), Scholar Rock’s treatment for spinal muscular atrophy (SMA) that the company hopes will become the first muscle-directed therapy for the disease.
The other two new PRIME-designees were Rocket Pharmaceuticals’ RP-L201 gene therapy for the rare pediatric disease, leukocyte adhesion deficiency-I (LAD-I), and Pfizer’s elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody for treating multiple myeloma.
AUT01, apitegromab, RP-L201 and elranatamab were accepted on PRIME during the latest monthly meeting of the EMA’s human medicines committee, the CHMP, which took place on 22-25 March. Four other applications for a PRIME designation were denied.
By making it onto the scheme, Autolus, Scholar, Rocket and Pfizer have managed to meet PRIME’s tough eligibility criteria by demonstrating the potential for their products to benefit patients with unmet medical needs based on early clinical data.
Companies accepted onto the scheme are offered enhanced support from the EMA to help optimize their development plans and generate robust data. They can also expect that the eventual EU marketing application for their product will be eligible for review under the agency’s accelerated assessment mechanism – though it is not uncommon for products that have come through PRIME to be reviewed under standard timelines.
‘Compelling’ AUT01 Data
AUT01 is a potentially curative therapy for relapsed/refractory ALL. According to Autolus, the product may be able to overcome the limitations of current CD19 CAR T-cell therapies. “Designed to have a fast target binding off-rate to minimize excessive activation of the programmed T cells, AUTO1 may reduce toxicity and be less prone to T cell exhaustion, which could enhance persistence and improve the ability of the programmed T cells to engage in serial killing of target cancer cells,” the UK company said.
According to Autolus, AUT01 produced “compelling activity and safety data” in the company’s ALLCAR Phase I clinical trial. (Also see "Autolus Forced To Slim Down, But Believes CAR-T Has 'Transformational' Potential" - Scrip, 6 Jan, 2021.)
AUTO1 is currently being investigated in the ongoing FELIX Phase Ib/II study in adults with relapsed/refractory ALL.
FELIX is a potential pivotal study, the company said. It will have a short Phase Ib component prior to proceeding to a single arm Phase II clinical trial. The trial will enrol approximately 100 patients across 30 centers in the US, the UK and Europe.
Muscle-Directed Therapy: Apitegromab
Apitegromab, which has received EU orphan drug status, is a selective inhibitor of the activation of latent myostatin, a growth factor that is expressed primarily in skeletal muscle cells to inhibit muscle growth. Scholar believes the inhibition of the activation of latent myostatin with its drug may promote a clinically meaningful improvement in motor function.
Earlier this month, the company released the 12-month topline results from its Phase II TOPAZ study of apitegromab in patients with Type 2 and Type 3 SMA. The findings, it said, provided further support towards establishing its product “as a potential first muscle-directed therapy for patients with SMA.” (Also see "Scholar Rock Sees Phase III Path For SMA Drug" - Scrip, 6 Apr, 2021.) Scholar plans to start a Phase III registrational trial by the end of 2021.
Apitegromab is being developed and investigated for use as an add-on treatment to any approved survival motor neuron (SMN) upregulator therapy or as a monotherapy in certain clinical settings.
Analysts from Cowen believe that Scholar’s drug has “significant potential” to improve the functional capacity of SMA patients, even after treatment with disease-modifying therapies such as Novartis’s Zolgensma (onasemnogene abeparvovec) gene therapy and Biogen’s antisense oligonucleotide drug, Spinraza (nusinersen).
In February, Cowen analysts said that despite the recent approvals of Spinraza and Zolgensma there remained substantial unmet need for SMA patients. “We believe apitegromab has the potential to be the first muscle-directed therapy to reverse or prevent muscle atrophy in patients with all types of SMA and further improve patient outcomes as a monotherapy or when used in conjunction with SMN upregulator therapy or gene therapy.”
RP-L201 & Elranatamab
The PRIME designation for Rocket’s RP-L201 was granted based on encouraging preliminary safety and efficacy data from the company’s ongoing Phase I/II clinical trial.
RP-L201 has been granted EU orphan drug status. LAD-I is a rare, autosomal recessive pediatric disease. Infants with a severe form of the condition suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia.
Data from the ongoing Phase I/II clinical trial were released last December. They demonstrated evidence of safety and efficacy in three pediatric patients with severe LAD-I, Rocket said. “These patients have shown sustained CD18 expression exceeding the 4-10% threshold associated with survival into adulthood and similarly encouraging peripheral blood vector copy numbers. RP-L201 was well tolerated with no drug product safety issues reported with infusion or post-treatment.”
Pfizer’s elranatamab (PF-06863135) is also showing promise.
Last December, the company presented encouraging data from MagnetisMM-1, an ongoing, Phase I trial of the drug. The data demonstrated manageable safety and high response rates in patients with relapsed/refractory multiple myeloma including three patients whose disease relapsed on or progressed after prior BCMA-targeted therapies. “At the highest dose level, which informed the dose selected for the Phase 2 study, 83% of patients achieved a clinical response,” Pfizer said. “Safety was manageable across all subcutaneous dose levels with no dose-limiting toxicities observed.”
In February, Pfizer initiated its pivotal Phase II MagnetisMM-3 Trial of elranatamab in multiple myeloma. The study’s estimated primary completion date is June 2022.
Elranatamab is administered subcutaneously, an approach that the company explains is intended to allow higher doses than intravenous administration without increasing adverse events.
Failing To Make The Grade
The four applications for PRIME designation that were rejected last month were for drugs for treating: pseudomyxoma peritonei – peritoneal mucinous tumors; Olmsted syndrome; blastic plasmocytoid dendritic neoplasm; and biochemical relapsed prostate cancer without metastatic disease after radial prostatectomy or definitive radiation therapy.