European Approval Process Coverage Winners & Losers: A Deep-Dive Into The EMA’s PRIME Scheme Executive Summary marketing approval, including Europe’s first two Nine of the 70 medicines for unmet medical CAR T-cell based treatments and some cutting- needs that have to date won a place on the edge gene therapies. European Medicines Agency’s PRIME scheme are now approved for sale in the EU, and two more In this article, the Pink Sheet explores how PRIME approvals are expected soon. Meanwhile, most has been faring in the four years it has been applications for a “priority medicine” designation operating. are still missing the mark. Optimizing Development Plans Developers of products that win a place on the scheme are offered enhanced support from the Drug developers are continuing to show a lot EMA to help them optimize their development of interest in the European Medicines Agency’s plans and they may also secure review under priority medicines (PRIME) scheme and the the agency’s accelerated assessment mechanism advantages it offers. when they file the marketing application for their product for evaluation. Since the scheme was launched in 2016, the EMA has received over 300 applications from The scheme has tough eligibility criteria. companies seeking a PRIME designation for their Applicants must convince the EMA that their early-stage investigational products. The aim of investigational product has the potential to the program is to get drugs for unmet medical benefit patients with an unmet medical need, needs to patients faster by helping developers based on early clinical data. optimize their development plans and increasing the likelihood of having their products fast-tracked As of late July 2020, the EMA had received when they are eventually filed for regulatory 308 applications for entry onto PRIME. Of the review. applications reviewed, 70 have won PRIME designation and 228 were turned down. Ten Almost half of the medicines that have been applications were discarded and not reviewed. accepted onto scheme have been advanced therapy medicinal products (ATMPs). PRIME- Crossing The Finishing Line designated products cover a wide range of Nine PRIME-designated products have so far therapeutic areas – with oncology and hematology received pan-EU marketing approval. These medicines making up the largest share. Most are include the CAR T-cell cancer therapies Kymriah being, or have been, developed almost equally by and Yescarta, and the gene therapies Zynteglo small and medium-sized enterprises (SMEs) and and Zolgensma for treating transfusion- bigger pharma companies. dependent β-thalassemia and spinal muscular atrophy respectively. The table below lists the nine To date, nine products that were awarded products that have been approved. PRIME designation have gone on to win pan-EU 2 / October 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) PRIME-Designated Products Approved In The EU As Of 17 August 2020 Six of the nine medicines were granted a accounting respectively for 27% and 19% of the conditional marketing authorization, which means total. Only five of the 32 applications targeting the companies are required to provide the EMA neurology have been accepted as have just two with more data post-approval. The products in of the 18 applications for cardiovascular diseases. question are: Rozlytrek, Hepcludex, Zynteglo, See bar char below for all the therapeutic areas in Zolgensma, Ervebo and Polivy. the applications. Oncology And Hematology Are The Winners Some 47% (33 products) of products accepted The applications that have been accepted onto the onto the scheme have been ATMPs. The EMA scheme cover a wide range of therapeutic areas, has previously observed that a large proportion with oncology and hematology medicines making of ATMPs are being developed by SMEs who up the largest share. Nineteen of the 70 PRIME- often lack experience of the regulatory approval designated drugs are for cancer and 13 are for process. treating hematology/hemostaseology conditions, 3 / October 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Regarding the remaining product types, 19 submitting applications in these markets.” (Also are small molecules (which the EMA refers to see “Adu-CAN-umab? Reading The Tea Leaves as chemicals), 15 are biologicals and three are For Biogen’s US Filing For Alzheimer’s Drug” - Pink immunological drugs. Sheet, 10 Aug, 2020.) While PRIME-designated products are being – or Vocimagene Amiretrorepvec have been – developed almost equally by SMEs Another product withdrawn from the scheme was and bigger pharma companies, there have been a Tocagen’s gene therapy for high-grade glioma handful of applications from academia, but these (HGG), Toca 511 (vocimagene amiretrorepvec). have all been turned down. The company’s Toca 511/Toca FC treatment last year missed the primary endpoint of overall Ten of the 308 applications were discarded survival compared to standard of care treatment without having been reviewed because they were and all secondary endpoints in a Phase III trial. deemed to be outside the scope of the scheme Tocagen has since merged with dermatology firm or to have a format and content inadequate to Forte Biosciences, but a statement from the latter support their review. in June does not mention any future plans for the HGG treatment. No Guarantees Five PRIME-designations have been withdrawn Emapalumab at the request of the companies involved, mostly Getting on and staying on the scheme also does because they had discontinued development. not necessarily guarantee EU marketing approval. Withdrawal from the scheme does not necessarily Gamifant (emapalumab), from Swedish Orphan spell the end of the road for a product. Biovitrum (Sobi), received PRIME designation in May 2016 and a marketing authorization Aducanumab application (MAA) for the product was submitted For example, aducanumab, Biogen and Eisai’s to the EMA for review in September 2018. investigational drug for treating Alzheimer’s Having reviewed the MAA, the agency last disease was among the first products to win a month recommended against approving the PRIME designation. The anti-amyloid agent was potential treatment for primary hemophagocytic later withdrawn from the scheme after producing lymphohistiocytosis. Sobi, which has already poor results in Phase III trials. These results were received US approval for Gamifant, said it announced in May 2019 and the companies said would appeal against the EMA’s decision. (Also they were discontinuing Phase III trials. A few see “Sobi To Appeal Against EMA Rejection For months later, Biogen surprised everyone by saying Emapalumab” - Pink Sheet, 24 Jul, 2020.) that a further analysis of the trial data had shown positive results and plans to pursue regulatory Two More Approvals In The Wings approval for the product were on again. In July Another two PRIME-designated products are 2020, the company said it had completed the expected to be approved soon – GlaxoSmithKline’s submission of a biologics license application multiple myeloma drug, Blenrep (belantamab (BLA) to the US Food and Drug Administration mafodotin), and Hansa Biopharma’s Idefirix for the approval of aducanumab and that it “has (imlifidase), for the desensitization of continued to engage in dialogue with regulatory highly sensitized patients who need kidney authorities in other markets, including Europe transplantation but are unlikely to receive a and Japan, working diligently toward the goal of compatible transplant. The EMA recommended 4 / October 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) that Blenrep and Idefirix be granted EU marketing European Commission, which usually takes approval in July and June respectively. The around two months to issue a formal approval. agency’s recommendations are sent to the The Fate Of PRIME Applications 5 / October 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) PRIME Applications By Therapeutic Area As Of 23 July 2020* EGFM - Endocrinology-gynecology-fertility-metabolism; IRT - Immunology-rheumatology-transplantation; NPIC - Neonatology-pediatric intensive care. *Out of scope applications are not included in this chart. Source: EMA 6 / October 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) This Year seven months of 2020 and 2019 are also similar, There is continuing interest in PRIME. at 82% (28 applications denied) and 76% (23 denied) respectively. In 2020 to date, the EMA has reviewed a similar number of applications for PRIME compared with The latest investigational drugs to receive PRIME the same period last year. designation are Adaptimmune Therapeutics’ ADP-A2M4 cell therapy for synovial sarcoma and Between January and the end of July this year, Imago BioSciences’ myelofibrosis treatment, the agency reviewed 34 applications versus 30 bomedemstat. applications in the first seven months of 2019. Six investigational drugs have made it onto the The applications from the two companies scheme this year, compared with seven during the were among seven such requests that the EMA same time period in 2019, a year that culminated reviewed in July – the other five failed to make the in 16 PRIME designations being granted. grade. The table below lists all the products that have made it onto the scheme this year. The rejection rates for the applications in the first Products Granted PRIME Designation In Jan-July 2020 Most Applications Denied For example, Adaptimmune’s ADP-A2M4 was PRIME’s high rejection rate is perhaps to be accepted based on clinical data from a Phase expected. As noted by the EMA in its 2019 I trial, which the company said demonstrated annual report, published in June 2020, the “compelling efficacy and early promising scheme is intended for only the most promising durability, with tolerable safety in patients medicines and the agency focuses its attention on with synovial sarcoma.” Based on these data, products that have the potential to bring a major Adaptimmune initiated its Phase II SPEARHEAD-1 therapeutic advantage. trial of ADP-A2M4, enrolling patients with advanced synovial sarcoma and myxoid/round As such, the entry criteria are strict.