PTC’s ‘Life-Changing’ Gene Therapy Among Nine Drugs To Win EU Thumbs Up
Executive Summary
The European Medicines Agency has delivered its verdict on the latest medicines it believes should be approved for marketing in the EU. By contrast, it has given the thumbs down to one biosimilar anticancer drug and its duplicate.
PTC Therapeutics’ Upstaza (eladocagene exuparvovec) has stepped closer to becoming the first ever treatment approved for the rare and fatal nervous system disorder, AADC deficiency, after the European Medicines Agency recommended that the one-time gene replacement therapy should be granted pan-EU marketing authorization.
Once the EMA’s recommendation is ratified by the European Commission, Upstaza will be the first approved disease-modifying treatment for AADC (aromatic L-amino acid decarboxylase) deficiency for patients 18 months and older and the first marketed gene therapy directly infused into the brain, said PTC.
Upstaza is among nine medicines that the EMA today said should be authorized for marketing in the EU.
The others include Xenpozyme (olipudase alfa), from Sanofi, for treating acid sphingomyelinase deficiency (ASMD), Eiger BioPharmaceuticals’ Zokinvy (ionafarnib), for children with progeria or progeroid-like syndromes, Cevenfacta (eptacog beta (activated)), from LFB Group, for treating bleeding episodes in patients with congenital hemophilia, and Kinpeygo, Calliditas Therapeutics’ novel oral formulation of budesonide for treating primary immunoglobulin A nephropathy (IgAN).
The remaining products recommended for approval were generic drugs: Sun Pharmaceutical Industries’ Ertapenem SUN (ertapenem), Gedeon Richter’s Ganirelix Gedeon Richter (ganirelix), Accord Healthcare’s Sitagliptin/Metformin hydrochloride Accord (sitagliptin/metformin hydrochloride), and Fresenius Kabi’s Sugammadex Fresenius Kabi (sugammadex).
A No For Tuznue And Hervelous
On the other hand, the EMA said that two products should not be approved. These were Prestige Biopharma’s Tuznue – which is a biosimilar version of trastuzumab – and its duplicate Hervelous, for treating certain forms of breast cancer and gastric cancer.
The agency said it considered that the manufacturing process for both drugs used during clinical testing differed from the process for commercial production of the medicines. “As a result, the studies presented did not provide enough evidence to show that the commercially produced medicine will be biosimilar to the reference medicine,” it said.
Therefore, the agency’s opinion was that the balance of benefits and risks of the drugs could not be established in the applied therapeutic context. Prestige has 15 days in which it can ask for a re-examination of the refusals. (Also see "Blow For Prestige As Trastuzumab Biosimilar Rejected By EMA" - Generics Bulletin, 20 May, 2022.)
The agency’s recommendations were published on 20 May. All 11 drugs had been up for an opinion on whether they should be approved during the latest monthly meeting of the EMA’s human medicines committee, the CHMP, which ran from 16-19 May (see sidebar). Opinions by the CHMP are sent to the commission, which has 67 days to make a legally binding decision valid throughout the EU.
Four of the drugs have EU orphan drug status: Upstaza, Xenpozyme, Zokinvy and Kinpeygo. Orphan designations must be reviewed by the EMA at the time of approval to determine whether the information available to date allows orphan status to be maintained and 10 years of market exclusivity to be granted.
Upstaza OK’d Under ‘Exceptional Circumstances’
PTC said it was “thrilled with the positive opinion from the CHMP” for Upstaza and was “eager” to bring the therapy to patients living with AADC deficiency.
Patients with AADC typically experience developmental delays, weak muscle tone and inability to control the movement of their limbs. AADC deficiency is a long-term, debilitating and life-threatening condition because it can lead to multiple organ failure.
“The difference Upstaza… can make is life-changing,” Paul Wuh-Liang Hwu, lead investigator at the National Taiwan University Hospital, said in a statement released by PTC. “Before therapy, affected children couldn’t even lift their head, but now many can sit, stand with help, feed themselves and some can walk and talk,” he explained.
AADC deficiency is ultra-rare. Around 1 in 118,000 people in the EU are estimated to have the condition.
Upstaza was recommended for approval under “exceptional circumstances,” a type of marketing authorization granted to medicines where the applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the condition to be treated is rare or because collection of full information is not possible or is unethical.
Medicines approved under exceptional circumstances are subject to specific post-authorization obligations and monitoring. The CHMP requested that PTC submit data to further characterize the long-term efficacy and safety of patients enrolled in the clinical trials, on the basis of a 10-year follow-up and a registry-based safety study on patients treated globally with the medicine.
The EMA’s recommendation for approval was based on the results of three trials including 28 children between the ages of 18 months and eight years and six months with severe AADC deficiency confirmed by a genetic diagnosis, the agency said. All trials were conducted with an unblinded single arm and historic control data from published studies was used as a comparator.
“The main favourable effects attained by the participants were head control and the ability to sit unassisted,” the agency said. “An ad-hoc expert group was consulted to discuss the clinical relevance of the motor benefits of treatment and concluded that efficacy had been demonstrated and is clinically meaningful.”
As for targeting other countries, PTC earlier this month said it planned to file the gene therapy for US review and approval in the third quarter of 2022.
Commenting on the EMA’s decision, the company said it was “important for the biotech community to have gene therapy products achieving approvals at regulatory bodies, as well as it being an important milestone for PTC that will help us build the gene therapy franchise and grow our revenue base.”
Xenpozyme Nod Hot On Heels Of Japanese Approval
Sanofi’s Xenpozyme, once approved by the commission, will become Europe’s first treatment for ASMD, a rare and progressive genetic disease that was historically referred to as Niemann-Pick disease types A (NPD A) and B (NPD B). The drug was approved for the first time in March, in Japan.
The drug is an enzyme replacement therapy designed to replace deficient or defective acid sphingomyelinase, an enzyme that allows the breakdown of sphingomyelin. Accumulation of sphingomyelin in cells can cause harm to the lungs, spleen and liver, as well as other organs, potentially leading to early death.
Xenpozyme is indicated for the treatment of non-central nervous system manifestations of ASMD in pediatric and adult patients, the EMA said.
In the US, the Food and Drug Administration has extended its review of the biologics license application (BLA) for the drug by three months, with a new target action date of 3 October.
Xenpozyme was developed by Sanofi under schemes that the EU, US and Japanese regulators run to speed up the development and approval of promising drugs for diseases lacking satisfactory treatments – ie, PRIME, Breakthrough Therapy Designation and Sakigake respectively.
The EU marketing application for the drug was reviewed under the EMA’s accelerated assessment pathway, which the agency reserves for drugs it deems to be of potential major public health interest, particularly from the point of view of therapeutic innovation.
Zokinvy Also Gets ‘Exceptional Circumstances’ Nod
Eiger’s Zokinvy is set to become the first treatment approved in Europe to treat Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies (PL - collectively known as progeria). Zokinvy was approved in the US as a treatment for progeria in November 2020.
HGPS and PL are devastating, ultra-rare, and fatal pediatric diseases that cause dramatically accelerated aging and premature death. The main cause of death from these conditions is heart attack or stroke due to severe hardening of the arteries. Most children die in their early teens due to severe cardiovascular complications, at an average age of 14.5 years.
If authorized in the EU, “Zokinvy will represent the only therapeutic option that has been proven to meaningfully extend the lives of children with HGPS – with the significant effect of extending their average life span by nearly one third," Eiger said.
As with Upstaza, the EU marketing authorisation for Zokinvy was recommended under exceptional circumstances.
Last week, Eiger said it had entered into an agreement with AnGes for the regulatory approval and commercialization of the drug in Japan.
Kinpeygo & Cevenfacta
Calliditas’s Kinpeygo, if approved by the commission, will be the first treatment in the EU for IgAN, a rare, progressive autoimmune disease of the kidney with a high unmet need. More than 50% of patients potentially progress to end-stage renal disease, the company said, noting that the drug would be marketed exclusively by STADA Arzneimittel.
Kinpeygo was recommended for conditional marketing authorization by the EMA. Conditional approvals may be granted based on less comprehensive clinical data than normally required, where the benefit of immediate availability of the medicine outweighs the risk inherent in the fact that additional data are still required, which the sponsor must submit within defined timelines.
In addition, Kinpeygo was classified by the EMA as a hybrid medicine – these rely in part on the results of preclinical tests and clinical trials of an already authorized reference product and in part on new data.
Kinpeygo, which was developed under the name Nefecon, received an accelerated approval in the US last December as Tarpeyo.
As for Cevenfacta, the EMA said that LFB’s drug should be approved for use in certain adults and adolescents (12 years of age and older) for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures.
In the US, the drug was approved as Sevenfact in April 2020.
Regarding the generic drugs that the EMA said should be approved:
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Ertapenem SUN is for treating ertapenem-susceptible bacterial infection.
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Ganirelix Gedeon Richter is for the prevention of premature ovulation in women receiving fertility treatment and who are having ovarian stimulation.
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Sitagliptin/Metformin hydrochloride Accord is a treatment for type 2 diabetes mellitus.
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Sugammadex Fresenius Kabi is for the reversal of neuromuscular blockade induced by rocuronium or vecuronium.