by Giuliana Miglierini
According to the 2021 Global Drug Delivery & Formulation Report, signed by Kurt Sedo, Vice President Operations, PharmaCircle LLC and published in a three-part series on Drug Development & Delivery, the Covid-19 pandemic seems to have had little impact on the regulatory approvals of new dosage forms and formulations. A positive sign from the pharmaceutical ecosystem, considering the difficulty to maintain normal operative conditions, the issues with international supply chains and the many hurdles to regulatory activities posed by the emergency.
According to Kurt Sedo, products newly approved by the FDA and based on new chemical entities have been the less affected, as they reflect a larger benefit for patients. On the other hand, are generics, together with new dosage forms and new formulations. Simple dosage forms continue to represent the great part of new approvals, while biologics prevail in terms of NCEs for injection.
The FDA approved in 2021 a total of 31 new products under the Biologics Licence Application (BLA) procedure, slightly more than in the previous two years. The increase is mainly linked to the higher number of vaccines and cell and gene therapies, while approval of biologic medicines maintained stable.
Approval trends by category of product
A marked decrease characterised Abbreviated New Drug Approvals (ANDA) (627 in 2021, vs 903 in 2020 and 962 in 2019). New Drug Applications (NDA) also slightly decreased. Analysing this category by type of product, the decrement is marked for new molecular entities and new dosage forms, while an opposite trend can be observed for new active ingredients and new formulations/new manufacturers.
As for administration route, the report indicates a marked prevalence of injection in all geographic areas (US 55%, EU 36%, JP 59%); oral drugs also continue to be highly represented. The author warns about the difficulty to reliably interpret the figures for European and Japanese approvals, as “The European Medicines Agency (EMA) approvals relate only to specific classes of pharmaceutical products and don’t capture the full range of products. The Japanese Pharmaceutical Medical and Medical Devices Agency (PMDA) published approvals are hard to access and properly assess”.
Looking more in detail at the injection route of administration, intravenous injectable products remain the leading category (US 39%, EU 38%, JP 38%), followed by subcutaneous injection. Simple solutions with or without a dedicated delivery device were the most commonly approved injectable simple dosage forms in 2021. Tablets and capsules remained the favoured oral dosage forms, while granules and pellets are especially represented in paediatric formulations.
Small molecules are the more represented category of active ingredients (US 64%, EU 74%, JP 52%), followed by antibodies and peptides; this last category of API offer the advantage of a possible formulation as non-injectable dosage form.
A deeper insight on the main approvals
Part 2 of the series debates the main products approved in 2021. The trend hints to a higher interest towards products and technologies targeted to wider patient populations and more diverse applications. According to Sedo, mRNA and gene therapy platforms have decrease their appealing due to need of validation for applications different than vaccines in the first case and safety and durability concerns in the latter.
Skytrofa (Ascendis Pharma) is a pegylated form of the growth hormone lonapegsomatropin-tcgd for injection or subcutaneous administration, using the dedicated rechargeable and reusable auto-injector. The weekly administration is the main advantage, overruling the need of daily injections.
Invega Hafyera (Janssen Pharmaceuticals), containing paliperidone palmitate as the active ingredient, has been approved in the US to treat adult schizophrenia by intramuscular injection every 6 months. Despite the parent molecule has already lost its exclusivity, Kurt Sedo highlights the remarkable lifecycle management of the Invega family of products, which allowed Janssen to maintain significant revenues for almost 20 years.
Tyrvaya (Oyster Point Pharma) is indicated to treat dry eye using the nasal delivery route. The formulation containing varenicline is administered using the Aptar’s CPS Spray Pump, representing the first approval for this type of technology platform. The possibility to overcome issues in treating ocular conditions connected to the difficulty many patients may experience with the administration of classical ocular drops is the main point of innovation.
Acuvue Theravision (Johnson & Johnson Vision Care) are contact lenses firstly approved in Japan and containing ketotifen to treat allergic conjunctivitis. In this case too, the approach may be replicated to administer other types of drugs in the eye. Issues may be represented by the difficulty of patients in using contact lenses and the need to stabilise the active ingredient to prevent leaching.
Cabenuva Kit (ViiV Healthcare) contains the combination cabotegravir – rilpivirine to treat HIV infection. Firstly, approved in Canada, it is administered monthly by intramuscular injection. Long-acting formulations can prove interesting to overcome compliance issues which may result in serious consequences for patients, as already proved in the case of hepatitis.
The monoclonal antibody Susvimo (anibizumab; Genentech) is formulated as a refillable ocular implant to treat wet acute macular degeneration. After implantation, the intravitreal injections using the Port Delivery System (PDS) occur every 6 months.
Other relevant technologies mentioned among new 2021 approvals include the Medicago Virus Like Particles (VLP) technology, which uses tobacco-related plants as bioreactors to produce noninfectious VLP that mimic the target virus, and LICA technology (Ionis), based on Ligand Conjugated Antisense (LICA) to favour the interaction of ligands and their respective receptors.
The Denali Transport Vehicle (TV) platform uses specific antibodies, enzymes, oligonucleotides, or proteins to link to the transferrin receptor of the blood vessel wall in the brain, thus providing a way to pass the blood-brain barrier by endocytosis.
MedRing (Ligalli) is a smart vaginal insert containing a miniaturised liquid formulation drug container with pump, battery, antenna, electronics, and sensors to monitor various biometric parameters (e.g. glucose or ovulation status).
Q-Sphera (Midatech Pharma) provides a bioencapsulation process using a microfluidic device to obtain discrete droplets without use of surfactants, toxic solvents, biphasic mixtures, shear, or heat forces.
Products in the pipelines
Part 3 of the series addresses the expectations for new approvals of products still in the pipelines The trend shows a higher percentage of early-stage products (research and pre-clinical phases), which is attributed to the higher interest of investors towards new companies able to fill the pipelines with early stage projects. The impact of Covid-19 has proved to be more relevant on projects at the clinical stage.
Small molecules still represent the main focus of development (59% in 2021/22), even if a drop has been observed from values recorded in 2015/16 (66%). Biological products may pose issues due to their highly speculative nature, suggests the report, while oligonucleotide and RNA products still represent only the 2% of the total in the pipelines; a more mature technology are antibodies (12%).
Cancer continues to be the leading therapeutic area of development, followed by infectious diseases and drugs to treat the central nervous system. The report indicates a very high attrition rate for anti-infectives under development, while many anti-cancer therapeutics in the pipelines may be me-too products pursuing validated therapeutic mechanisms. As seen above, injectable formulations maintain the leading position also for products under development (52%), followed by oral formulations.