2020 will go down in history as the year of the pandemic. Vaccine development is typically measured in years, not months, yet 2020 was the year where not only one vaccine but three, were made and approved for emergency use without compromising safety. Not only were these vaccines developed in record time, but a new era in vaccinology was also introduced – the mRNA vaccine.
Every year, we at NDA review the new therapeutic drug approvals in the EU and US from previous years to spot trends and assess the year that has passed. The data is taken from the EMA and FDA websites on the new approved products of 20201. In this review we include new therapeutic drug product approvals with new active substances (chemical, biological, biotechnology or radiopharmaceutical substance), new biological entities, new drug combinations, biosimilars, new active ingredients and vaccines, but exclude generic and duplicate applications.
The pandemic created an urgent need for a vaccine, but also for repurposing any existing drug that could mitigate the dangerous effects of severe COVID-19. This was taking place whilst countries and infrastructures were shutting down. 2020 was an exceptional year in the sense that these extraordinary circumstances did not hamper the innovation in drug development. A record-breaking 133 new therapeutic drugs were approved across the EU and the US and the medical value in patient care of these new therapies vastly exceeds their number. EMA approved an impressing total of 62 drugs, a major leap from previous years.
The approval process timelines in the two major jurisdictions, the EU and the US are significantly different, but products have been approved in both markets during 2020. Among many programs, these illustrate the incredible advances in treatments of life-threatening diseases and rare genetic disorders. Here we find Sarclisa (sanofi-aventis group), a targeted immunotherapy for multiple myeloma treatment given to adults who have received at least two previous treatments for their cancer and has worsened since receiving the last treatment. Givlaari (Alnylam Pharmaceuticals) is a medicine for treating acute hepatic porphyria in patients aged 12 years or over. This is a rare genetic condition resulting in the build-up of toxic porphyrin molecules in the body. Givlaari is a double-stranded small interfering RNA that causes degradation of crucial enzymes through RNA interference, reducing the elevated levels causing the patients porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures, and mental status changes. Ayvakyt (Blueprint Medicine) is a tyrosine kinase inhibitor that is used to treat adult patients with gastrointestinal stromal tumour (GIST) whose disease is caused by certain abnormal platelet-derived growth factor receptor alpha (PDGFRA) genes and cannot be surgically removed or has spread throughout the body (metastatic GIST).
Restrictions on international travel exposed weaknesses in supply chains, lockdowns prevented access to healthcare providers and prevented patients from accessing care and trial sites. According to GlobalData2 at the pandemic’s peak, between April and May 2020, more than 1,200 trials were delayed worldwide. Among the severely affected clinical trials, oncology and CNS were the therapeutic areas which took the hardest hit, however, as from June 2020, the decrease slowed down and these two areas were the only ones expected to fully recover by the end of the year3. The measures taken to adapt to the risks accompanying the pandemic were successful depending on the possibilities for the trials to convert to remote monitoring including conducting virtual or decentralized trials and the use of other non-traditional approaches that do not involve in-person visits. Telemedicine and eConsent are here to stay, opening up to more sites, bringing trials closer to the patient.
Advanced Therapeutics
Not too long ago, the idea of treating or even curing a disease through gene therapy, cell therapy or tissue engineered products was just a vision – a theoretical discussion. But today it is a reality that holds the promise of bringing life changing benefits to patients by directly targeting the underlying cause of the disease. Advanced therapy medicinal products (ATMPs) or regenerative medicine advanced therapies (RMAT) offer groundbreaking new opportunities for the treatment of diseases that conventionally have been considered incurable.
The COVID-19 pandemic has caused significant constraints globally in the delivery of cellular therapy, including partial closures of outpatient clinics, decreased infusion unit’s capacity, and a decrease in clinical staff. Interim guidelines for COVID-19 management were developed to help guide management in cellular therapy and stem cell transplantation recipients focusing on avoiding deferrals, even temporarily, as this could eliminate a potentially curative therapy4.
Moving forward with advanced therapeutics, expectations are still high, after the outstanding efficacy results of some licensed cell and gene therapy products. During last year we had additional players in the field: Zolgensma (Novartis Gene Therapies) is a gene therapy medicine for treating spinal muscular atrophy, a serious condition of the nerves that causes muscle wasting and weakness. It is intended for patients with inherited mutations affecting genes known as SMN1, who have either been diagnosed with SMA type 1 (the most severe type) or have up to 3 copies of another gene known as SMN2. Viltepso (NS Pharma) is an antisense oligonucleotide designed to bind to exon 53 of dystrophin pre-mRNA resulting in the exclusion of this exon during mRNA processing in patients with Duchenne Muscular Dystrophy. Exon 53 skipping is intended to correct the genetic mutation of the dystrophin protein allowing a functional, although shorter protein to be translated, thus maintaining muscular structure in these children. Libmeldy (Orchard Therapeutics) is used to treat children with metachromatic leukodystrophy (MLD), a rare inherited disorder in which a gene mutation causes potentially fatal damage to the nervous system and other organs. The active substance in Libmeldy is stem cells, (CD34+ cells), derived from the patient’s own bone marrow or blood, that have been modified to contain a copy of the corrected gene. During the year, FDA approved the third chimeric antigen receptor (CAR) T-cell therapy. Tecartus (Kite Pharma) is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed/refractory mantle cell lymphoma.
Successful Exploration of Novel Drugs
During 2020, the approvals of novel drugs, i.e., treatments based on new active substances, was somewhat lower than previous years. Out of the 133 new drugs, 69 were based on new active substances. Idefirix (Hansa Biopharma) is an antibody-degrading enzyme that eliminates immunological barriers and enables kidney transplantation in highly sensitized patients.
Retevmo (Lilly) became the first therapy specifically for patients with advanced RET-driven lung and thyroid cancers in 2020 followed by Gavreto (Blueprint Medicine), for treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. Zabdeno (Janssen-Cilag International) is a vaccine that protects adults and children aged one year and older against the Ebola virus disease caused by Zaire ebolavirus. It is used with another Ebola vaccine called Mvabea as part of a vaccine regimen.
Small Biotech
In 2020, small and medium sized enterprises (SMEs) contributed to 63% of the approved new therapeutic drugs. It was in 2017 when we first saw that small biotech’s exceeded big pharma’s contribution to new drug approvals. For 2020 half of these were for orphan indications.
Approved Orphan Drug Designations
Of the total number of the new drugs approved by the EMA and the FDA, 34% had an orphan designation. Some of the outstanding contributions to significantly benefit patients living with rare diseases include Fintepla, a medicine used in addition to other epilepsy medicines to treat patients from the age of 2 years who have Dravet syndrome, a rare type of epilepsy that begins in childhood and can continue into adulthood.
Oxlumo is a siRNA-drug used to lower the level of urine oxalate in children and adults with primary hyperoxaluria type 1 (PH1) which can lead to kidney damage. Tazverik is a drug used to treat a rare type of slow growing cancer called advanced epithelioid sarcoma. This small molecule inhibitor is to be used in patients 16 years and older when cancer has spread and cannot be completely removed by surgery. Sokinvy, is the first therapy for Hutchinson-Gilford progeria syndrome (HGPS), a rare, fatal, genetic condition with striking features resembling premature aging in children. This is a farnesyltransferase inhibitor that targets the accumulation of defective proteins leading to cellular instability and the process of premature aging.
Improvements within Precision Medicine
In a population of patients with the same clinical disease, the molecular causes may differ and can influence the treatment response. Targeted therapies are an effective treatment option for some patient subsets, as these treatments are based on the genetic makeup of the patient, rather than the symptoms. 2020 saw the approvals of several new products based on specific biomarkers to target the treatments to fit the patient. To further support precision and personalized medicine, the FDA cleared or approved nine diagnostic tests for oncology biomarkers, allowing physicians to detect actionable biomarkers in patients with cancer5.
Qinlock, kinase inhibitor is used to treat adults with advanced gastrointestinal stromal tumor (GIST) who have received 3 or more prior treatments for their GIST.
Calquence (AstraZeneca) a next-generation selective Bruton’s tyrosine kinase (BTK) inhibitor, has been approved for the treatment of patients with chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults., Rozlytrek, for people with NTRK fusion-positive solid tumors and for those with ROS1-positive advanced non-small cell lung cancer. This tumor-agnostic therapy treat cancer based on the cancer’s genetic and molecular features without regard to the cancer type or location. Trodelvy is a drug for the treatment of adults with triple-negative, metastatic breast cancer. Triple-negative breast cancer has no receptors for the hormone estrogen and progesterone, as well as no receptors for the HER2 protein which has previously put limitations on treatment of these patients.
Expedited approval of novel drugs
Agencies are working hard to increase the patient access of important medicines where there is huge unmet medical need. In the US, 33 new therapeutic drugs were approved through fast track, breakthrough, accelerated approval or priority review approval. Just as the previous year, over half of these were oncology products. In the EU seven expedited approvals of new therapeutic drugss were granted, however no trend towards any particular therapeutic area could be seen. Blenrep is a cancer medicine used to treat multiple myeloma, Danyelza is indicated for the treatment of paediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. Pretomanid FGK is a medicine for treating adults with extensively drug-resistant tuberculosis.
Project Orbis
On the subject of oncology, one interesting new approach for expedited approvals is Project Orbis, a pilot framework for parallel submission and review of oncology products that was launched by the FDA Oncology Center of Excellence in 2019. The first new drug approved within Project Orbis was Tukysa (tucatinib) in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adult patients with advanced forms of HER2-positive breast cancer that cannot be removed with surgery, or has spread to other parts of the body, including the brain, and who have received one or more prior treatments6. The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, Health Sciences Authority (HSA, Singapore) and Swissmedic (SMC, Switzerland) on this review. During its first year (June 2019-June2020), Project Orbis processed a total of 60 oncology marketing applications, resulting in 38 approvals, 28% of them new active substances7.
Emergency Use Authorization (EUA)
An additional pathway for getting therapies to patients in need is the Emergency Use Authorization (EUA) in the US. It has been relatively rarely used, its most extensive use was in combating the H1N1 swine flu pandemic of 2009 by authorizing medical equipment and existing influenza drugs8. Since February 2020, as the pandemic was declared a national health emergency, FDA has issued nearly 400 EUAs for personal protective equipment, medical equipment, in vitro diagnostic products, drug products, and vaccines. There are also EUAs which have been revoked since the beginning of the pandemic. One example is hydroxychloroquine, a malaria drug that according to a small study was an effective COVID-19 treatment but further research determined the drug was not effective and the risks of taking it outweighed any benefits. Veklury (remdevisir, Gilead Sciences) an antiviral approved for COVID-19 treatment has been granted EUA and conditional approval in the EU.
Blockbusters
Although many approvals during the last year are meeting the needs of rare diseases, there is however an opposite end of the spectrum, the blockbusters targeting common medical problems in a large patient population. One of the most anticipated approvals of 2020 was Leqvio (Novartis), a first-in-class siRNA to lower cholesterol with two doses a year. Leqvio was approved in the EU, but the US process is delayed since the FDA was unable to inspect due to COVID-19 travel restrictions9. Zeposia (Bristol-Myers Squibb) is already tipped for blockbuster sales in relapsing remitting multiple sclerosis and recent data suggest that there may be another future indication in ulcerative colitis10. Rimegepant (Biohaven Pharmaceuticals) is an oral treatment for acute migraine in adults. Palforzia is an oral immunotherapy to help reduce the severity of allergic reactions to peanuts, including anaphylaxis, in children ages four to 17.
NDA supported over 40% of the approvals in the EU
In 2020 life as we know faced a major disruption. For biopharma, the efforts to respond to the pandemic overshadowed many aspects of development, manufacturing, and quality compliance. Still, after adjustments the field kept on delivering and a record-breaking number of new approvals saw daylight. Being a regulatory advisor, NDA has been able to help these manufacturers through these challenging times, to bring medicines to the world. During the year, we kept a strong presence in the EU regulatory arena and supported 42% of the new products approved. We are proud to have been able to aid the regulatory process of several advanced therapies, novel/orphan drugs and through Project Orbis expedited treatments for serious oncology conditions.
Data collection and disclaimer
The data was gathered from the EMA and FDA official websites, as reported on the EMA and the FDA official websites in January 2020. As it is challenging to pull together data from two regions with different classification and reporting styles some general inclusion and exclusion criteria to create consistent indicators of the yearly trends in the EU vs. the US has been applied. The above article provides an overview of the key findings and an analysis of what the data means for the industry. The data is also visually represented in an infographic. As experience tells us, the final number of approvals reported normally fluctuates for some time after the end of the year, as the Agencies go through their house keeping processes. There could therefore be some slight changes to the findings outlined in this report before the data is completely finalised.
References
- The data was gathered from the EMA and FDA official websites, as reported on the FDA and the EMA official websites in January 2020.
- https://www.globaldata.com/49-clinical-trial-disruption-due-slow-enrollment/
- https://www.clinicalleader.com/doc/how-has-covid-impacted-the-clinical-trial-pipeline-0001
- https://www.tctjournal.org/article/S1083-8791(20)30217-2/fulltext
- http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/PM_at_FDA_The_Scope_Significance_of_Progress_in_2020.pdf
- https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-drug-under-international-collaboration-treatment-option-patients-her2
- https://clincancerres.aacrjournals.org/content/26/24/6412.long
- https://covidseries.law.harvard.edu/covid-19-and-the-fda-emergency-use-authorization-power/
- https://www.evaluate.com/vantage/articles/news/snippets/novartiss-leqvio-delay-could-last-year
- https://news.bms.com/news/corporate-financial/2020/European-Medicines-Agency-Validates-Bristol-Myers-Squibbs-Application-for-Zeposia-ozanimod-for-the-Treatment-of-Ulcerative-Colitis/default.aspx