With over 7,000 medicines in development, new treatments will continue to change patients’ lives, slowing disease progression, avoiding illness and reducing overall costs for healthcare systems. But developing a new medicine is a long, complex and risky process with no guarantees of success. Over the coming weeks, we look at a number of new medicines and the role that pharmaceutical incentives (or IP) have played in their development.

Chiesi and Holostem Terapie Avanzate have jointly developed Holoclar, the first stem-cell-based product to be approved in Europe. Chiesi licenses the international marketing authorization for Holoclar; the treatment is manufactured by Holostem.

Holostem is a spin-off company of the University of Modena, Italy, with around 70 employees. It was founded in 2008, and is partly owned by Chiesi and the scientists Michele De Luca and Graziella Pellegrini. The company is entirely dedicated to the development, manufacturing, registration and distribution of Advanced Therapy Medicinal Products (ATMPs) based on cultures of epithelial stem cells for cell and gene therapy. Chiesi was founded in 1935 in Parma, Italy. From its headquarters there, the company, currently employing around 5,100 staff, is active internationally in the fields of respiratory, neonatology and special care/rare diseases.

Changing patients’ lives with an innovative novel treatment

Holoclar is used to treat moderate-to-severe forms of limbal stem cell deficiency (LSCD) caused by burns, including chemical burns, to the eyes. If left untreated LSCD results in chronic pain, burning, photophobia (eye discomfort in bright light), inflammation, corneal neovascularisation (new blood vessels growing across the front of the eye), stromal scarring and the reduction or complete loss of vision.

It is essential that the cornea, the transparent layer in front of the eye covering the pupil (the black part) and the iris (the coloured part), remains transparent to see properly. Corneal cell renewal and repair are dependent on the cells present in the limbus between the cornea and the conjunctiva. Thermal or chemical burns to the eye can destroy the limbus, causing a deficiency of limbal stem cells. The cornea becomes opaque after an invasion of cells from the conjunctiva. Conventional corneal transplants are an ineffective treatment in such cases. Holoclar comprises limbal cells derived from a LSCD patient, provided that a small portion of limbus remains in one of the eyes. The cells are grown in a laboratory, positioned over a fibrin scaffold shaped similarly to a contact lens, and transplanted into the same patient’s affected eye(s) to repair the damaged corneal surface and restore its functions. In more than 70% of treated patients, a stable and transparent surface of the cornea was restored and results maintained long-term. Patient’s eyesight can be recovered using this innovative treatment (alone or in conjunction of a corneal transplantation in case of damage extending beyond the corneal surface), even several years after the accident.

Incentives are key for bringing the innovation to patients faster

Because the number of patients with limbal stem cell deficiency due to burns to the eyes is low, Holoclar was designated orphan medicine status in November 2008. It was conditionally approved by the EMA in February 2015, and Chiesi, together with Holostem, received marketing authorisation in Europe in 2016. In August 2017 the UK’s National Institute for Health and Care Excellence (NICE) recommended Holoclar for commissioning (clinical use) by the National Health Service. Holoclar was rewarded with the 2016 Prix Galien’s Orphan Product Award.

Both Chiesi and Holostem – since it is partly owned by Chiesi – are considered large enterprises, therefore no SME incentives applied to the development of Holoclar.

In general, Chiesi uses financial incentives like national and European grants wherever possible, including the European framework programmes FP 7&8, the IMI(Innovative Medicines Initiative), and PUMA (Paediatric Use Marketing Authorisation).
Holostem received a research grant from the Italian government for their innovative portfolio.

The latter was of strategic importance to Chiesi in their decision to partner with Holostem.

The formal orphan designation for Holoclar was another key factor for Chiesi. Medicines with orphan designation (OD) benefit from the incentive of ten years’ market exclusivity once they are approved for marketing in the European Union. This protects them from market competition with similar medicines and similar indications once they are approved and is intended to encourage the development of medicines for rare diseases.

Equally important was access – even at no cost – to multiple protocol assistance meetings for OD medicines, Chiesi reports. Particularly for unprecedented innovations such as the Holoclar stem cell therapy, discussions with EMA committees about the clinical study plans and rationale lead to a thorough mutual understanding that can speed up the approval process for the benefit of patients. For Holoclar these discussions led to conditional approval through the adaptive pathway. The adaptive pathways approach is part of EMA efforts to improve early and progressive patient access to new medicines. It allows market authorization for treatments in areas of high medical need where the benefit of immediate availability outweighs the risk of less comprehensive data than normally required. For Holoclar therapies, it is difficult to collect data via traditional routes, and clinical trials take a long time due to low patient numbers. Conditional approval is critical for patients to be able to benefit from the novel treatment, while Chiesi, as the sponsor, gathers evidence from real-life usage to generate or supplement clinical trial data.

A pediatric investigational plan (PIP) has been agreed with the EMA for Holoclar. Applicants can request scientific advice for the preparation of a PIP from the EMA, which is free of charge for questions relating to the development of paediatric medicines. They can also follow up a PIP with scientific advice on, for example, combined adult and paediatric development in regard to PIP requirements. For orphan medicines, the incentive is an additional two years of market exclusivity.

IP protection is also very important to Chiesi. The company therefore protects all its products with patents, covering every possible aspect: the active compound and its uses, but also its formulation and its manufacturing processes. Holoclar has IP protection covering specific technical elements of the manufacturing process and the fibrin bio-scaffold.

IP rights and EU pharmaceutical incentives enable ongoing innovation for patients

Not least thanks to the various incentives that help to enable better lifecycle management of novel treatments and some financial security, Chiesi will continue to explore innovation opportunities in all areas, including the digital domain, with the aim of focusing even more closely on the patient. Personalised medicines and integrated healthcare are Chiesi’s main goals for tomorrow. The company will continue to concentrate on high unmet medical needs and providing better answers than are currently available (or unavailable), focusing on better treatments for patients in need that go beyond traditional drugs.

A short history of the first stem cell-based product approved in Europe

– Chiesi founded in 1935 in Parma, Italy

– launch of Curosurf, the Respiratory Distress Syndrome (RDS) rescue treatment in premature infants, in 1992

– launch of Foster with Modulite Technology for the maintenance treatment of asthma and COPD in 2006

– Holostem founded in Modena in 2008

– Marketing authorisation for Holoclar, the first stem cell-based product approved in Europe in 2016, together with Holostem

– launch of Trimbow, the first triple combo for COPD, in 2017.