What crucial trends are driving the industry?
Having sequenced the genome around 2003 was one of the early steps towards eradicating modern plagues like cancer, Parkinson’s or autoimmune diseases, and there are many, many more steps to follow. Today, when biomedical researchers aspire to restore of body functions in patients completely we speak of “regenerative medicine”. The ambition is to achieve a healthy condition with a vision to renew complete organs one day. Building upon the first non-clinical success of the early 2000’s we have only seen a small number of therapies coming to the market yet.
Treatment approaches are often multidisciplinary and involve a range of cutting edge technologies including genetic engineering. Breakthroughs have been achieved that affirm the approach but significant challenges remain. Step by step, the field is coming out as one megatrend of the new century: with today’s value estimated somewhere around USD 500 millions, the conservative forecasts already range from USD 50-70 billions around 2020 (Source: Allied Market Research, 2013; George Osborne, Finance Minister UK, speaking to The Royal Society, 2012).
When the EMA (European Medicines Agency) had regulated the increasing number of novel therapies under development, a regulatory framework was established for gene therapy, cell therapy and tissue engineering. The category of Advanced Therapy Medicinal Products (ATMP) was established through Regulation 1394 which is having its 8th anniversary by November this year. Basic regulatory requirements were laid out to align science with the regulator’s emerging requirements to issue a Marketing Authorization.
For the “nascent field of biomedicine” offering new opportunities for the “treatment of diseases and dysfunctions of the human body” (Source: Regulation 1394) standardization of a regulatory pathway is somewhat limited. The gap was bridged by an approach to partner early in the process with scientists and companies working in the field. Hence the EMA’s “Committee for Advanced Therapies (CAT)” was “established in accordance with the Regulation 1394” to provide “non-routine” guidance for upcoming applicants. Collaborative procedures are ATMP classification of proposed treatments and certification of quality and non-clinical data for small and medium size companies. Further the CAT participates in agency procedures to assist the CHMP which involves preparing draft opinions on Marketing Authorization Applications.
What market segments will experience the most growth and why?
To date five products have obtained EMA marketing authorization under this regulation. The products are truly different and truly represent the wide scope of the category:
Oct-2009: ChondroCelet® (Tigenix) based on live autologous Chondrocytes for cartilage repair,
Nov-2012: Glybera® (UniQure) based on genetically engineered adeno-associated virus for treatment of lipoprotein lipase deficiency
Jul-2013: MACI®, matrix applied autologous chondrocytes (Genzyme) based on autologous chondrocytes for full thickness cartilage repair,
Mar-2015: Holoclar®, ex vivo expanded autologous human corneal epithelial cells containing stem cells, (Chiesigroup/Holostem) to replace damaged cells on surface (epithelium) of the cornea caused by burns, including chemical burns, to the eyes in adult patients.
May-2015: Provenge® (Dendreon) based on incubated dendritic cells for treatment of prostate cancer,
Number six is on its way with Imlygic® (talimogene laherparepvec, Amgen) receiving positive opinion on October 23rd of 2015. Imlygic is based on herpex simplex virus-1 that is genetically engineered to target cancer cells and produce the protein GM-CSF on expense of the tumor cell’s energy, eventually overwhelming the cell and causing it to die. In a second effect it also stimulates the patient’s immune system to recognize and destroy tumor cells.
Imlygic® will be approved for the treatment of adults with melanoma that cannot be removed by surgery and that has spread either to the surrounding area or to other areas of the body (regionally or distantly metastatic) without affecting the bones, brain, lung or other internal organs.
What are the key challenges?
The multidisciplinary approach of regenerative medicine is as powerful as it is complex and exposed to a multitude of challenges in different areas:
- Lack of standardization for process and quality controls and safety criteria,
- Uncertainty over translational pathway,
- Limited flexibility in clinical trials framework,
- Potentially reluctant clinical networks and difficult access to patients,
- Scale-up and logistics difficulty,
- Inadequate health technology appraisal methods,
- Securing IP,
- Attracting investments
(Source: Economic & Social Research Council, 2015)
Although the European Marketing Authorization of ChondroCelet® was renewed for another 5 years in May 2015, Tigenix has a patients base of only 1,000 treatments. The competing treatment of micro-fracturing remains a serious choice for clinicians to date and the stock price of the company has not yet lifted off.
Glybera® operates in a super-orphan indication with serious limitations on the eligible patient population. With USD 1 million for the once-in-a-lifetime treatment it is the world’s most expensive drug. Returns for the company are yet limited but the US-market entry is still ahead.
Provenge® had received its first hit from cost utility assessments and later was knocked out in Europe by two new treatments with small molecules. Dendreon had withdrawn the marketing authorization for commercial reasons and was bought by Valeant after filing for bankruptcy.
Getting the science piece right does not always make a successful business case. Whatever the setbacks are, these are always lessons learnt while regenerative medicine remains the biggest promise to patients suffering from diseases with no curative treatment option. This includes autoimmune diseases, cardiovascular repair, curative treatments of genetic or congenital defects, immuno-oncology, metabolic diseases and even repair of degenerated or damaged tissues (e.g. functional regeneration of muscle in incontinent patients.
The setback of Provenge® was somewhat counterintuitive for investors in the field. But immuno-oncology remains a hot item fired also by the expected approval of Imlygic®. The regenerative medicine landscape in Europe is dominated by SMEs (Source: Regenerative Medicine in Europe Project, 2011) with larger corporations slowly participating. Only 5 or 6 countries have relevant levels of activity in regenerative medicine with a majority of companies operating in France, Germany or UK. In Europe the UK is a suitable example how ATMP and the field of regenerative medicine is being developed through significant service infrastructure and other support to foster ATMP (https://ct.catapult.org.uk). The government’s total commitment for the first stage of developing regenerative medicines in UK was GBP 40 million. The ambitious plan aims at annual savings of GBP 1 billion in healthcare cost including lost productivity and an economic impact of GBP 5 billion and generation of 15,000 jobs with scientific qualification for medium to long term.
Concepts of risk based approach and quality-by-design must be thoroughly designed to meet regulatory requirements. The certification procedure for quality and non-clinical data by the CAT can provide guidance. Regulatory requirements are still emerging to stand up to the complexity of products and technologies used. In many cases GMP and especially scale up from lab bench to clinical batch size already are significant challenges regarding robustness of processes and comparability of product at different scales.
Significant challenges remain in the field. The novel mechanisms-of-action trigger demand for clinical and non-clinical data generations outside the usual focus. Due to the highly specific biological processes involved in the mechanisms, translation of non-clinical data to the human condition and extrapolations of safety related information from non-clinical data is challenging. Long-term safety data are often limited and this may lead to curtailing the eligible patient population to higher symptoms severity only.
The EMA has opened an “Adaptive Licensing” pathway to help solve this issue (http://www.ema.europa.eu) where applicants can find support from the regulator for a prospective planning of staged expansion of the target patient population through planned licence adaptations. This pathway makes use of existing regulatory processes within the EU framework to organize a life-cycle approach addressing the “evidence versus access” balance.
Another relevant item for many ATMPs are the EMA regulatory tools for early access. These include accelerated assessment and conditional approval. Key success factors for grant of early access are addressing unmet patient needs and high clinical relevance/major public health impact. The process is facilitated through appropriate planning of the development and detailed description of relevance of treatment outcomes. Early involvement of the regulator is crucial.
The pipeline is slowly but steadily expanding with more than 100 research products completing classification as ATMP through the CAT. While 5 MAs were granted a sixth is on the way. With Imlygic® US biotechnology giant Amgen is again in the role of the pioneer, this time first mover in US and Europe in the new category of immuno oncology. Also China demonstrated significant capabilities with the first two oncolytical viruses marketed Gendicine® and Oncorine® by Shanghai Sunway Biotech.
Much is to be expected from a large number of start-ups around the globe that work on similar products with over 400 clinical trials ongoing in the US and estimated 100 in Europe. Currently, in Japan, circa 15 clinical trials are ongoing in the field and the recent modifications of the regulatory pathway in Japan are likely to fuel projects there quickly.