Advanced Medicines: Making it to Market
We’ve learned a number of lessons when it comes to developing and manufacturing cell therapies, including the importance of keeping our eyes on the end goal of commercial manufacturing – even at the earliest stages.
Miguel Forte |
I think it’s fair to say that some of the first cell therapies to hit the market have been a little rushed – but with good reason; don’t we all want to bring life-saving products to patients as quickly as possible? In clinical trials, positive results demonstrated in patients have been the primary focus and so potential issues that have arisen haven’t necessarily been given the full attention they deserve. During a cell therapy clinical trial, for example, it is not uncommon for companies to make an exception and treat a patient with a product that would not be released at a commercial manufacturing level (depending on the problem) – particularly when the experimental therapy may be a patient’s only chance of life. When it comes to scaling up production, a manual and complicated process that worked for a small number of patients becomes a problem and questions also arise about how exactly you define product characteristics.
When the industry began pursuing biopharmaceuticals, they were described as being “three dimensional” – but cell therapies go a significant step further in terms of complexity and can be said to have a life of their own. Putting process controls in place when you have huge inherent variability from different patients’ source materials is difficult. And yet, despite the challenges, we’ve already seen fantastic results in the clinic. Continuing to learn from marketed cell therapy products and developing new solutions will allow us to continue to improve the quality of life of cancer patients globally.
Zelluna was built on the back of 30 years of research carried out at the Norwegian Radium Hospital on T cell receptors (TCRs) that began in the early 1990s. Today, we are focused on developing TCR-based adoptive immunotherapies and we have created a varied portfolio of both CD4 and CD8 T-cell therapies, with the intention of directing them against TGFβRII frameshift mutations and the universal cancer antigens, hTERT and RAS. In essence, this allows us to tackle a plethora of cancer types. Our lead TCR candidate, targeting hTERT, is expected to enter sponsor studies in 2020 and several of our other candidates are at the preclinical trial stage.
When I accepted the position of CEO at Zelluna Immunotherapy (see sidebar: Zelluna Ambitions), my first move was to hire a Chief Technology Officer. Why? In my opinion, manufacturing is crucial. As an industry, we are still learning about how best to manufacture these promising therapies and discovering the best technologies for the job. We can’t afford to wait until it’s time for commercialization; manufacturing and scale up must be considered early on so that you can reach patients smoothly. Because of this, my second move was to develop our short and long-term manufacturing strategies. I decided early on that it would be best to open our doors for discussion with organizations that could help with our process development, ensuring that we were ready for manufacturing when the time came.
At recent conferences I’ve attended, one of the hot topics on the minds of budding advanced therapy developers is outsourcing. Some people are of the opinion that it can be exploitative; however, it is often the only option available to small and medium companies. In fact, roughly 60 percent of companies outsource their manufacturing processes to CDMOs. Most of us rent our first home rather than buy it and the same logic can be applied when choosing to use the manufacturing facilities of CDMOs! Certainly, working with a CDMO is a good de-risking strategy and can free up valuable cash flow for the sponsor company. But the pros and cons of going it alone versus outsourcing should always be considered; for example, with outsourcing, you are not always in full control and the price per unit may be more expensive. If you do decide to go down the outsourcing path, just make sure the company is a good cultural fit; a CDMO will always have a mind of its own but there needs to be good synergy in beliefs and working practices to foster a long-term relationship.
The best advice I can offer? You always need to have the long-term perspective in mind. You don't manage your business today; you manage your business with a forward-looking perspective. In an ideal world – with endless investment(!) – we would all want to build our own manufacturing facilities because we would retain the value. In most cases, however, we must accept the risks and consider what long-term commitments are appropriate.
Our conversations with external organizations helped us to evaluate options and integrate solutions, such as automated closed systems, into our manufacturing plans from the outset, ensuring that we would be able to produce cost effective, easy-to-use products as and when we reached these stages of the drug development pipeline. Automated and closed systems are well accepted as being the best way forward for manufacturing cell therapies and it pays to consider this early on.
Capturing a moment in time
The road to commercialization is rarely free from obstacles for any therapy, but for advanced medicines, such as cell and gene therapies, there is still much more for us to learn and, therefore, potentially more hurdles in our way. In development, processes can be tweaked and adjusted, but once you reach approval, the regulators approve a “photograph” – and that photograph must be repeated perfectly again and again for each batch. As you reach the commercialization stage, you need to ensure your process is robust and repeatable. Regulators aren’t interested in the negatives you’ve produced – they want the final, perfect, polished and impactful photograph. It’s easy for companies to get ahead of themselves because their product offers promise, but if you don’t have a plan for manufacturing and commercial roll out then you’ll hit many more bumps in the road.
Some have said that regulation in the pharmaceutical industry borders on being too stringent, but ensuring public trust should always be at the forefront of all of our minds when developing these exciting therapies (see sidebar: A Little Knowledge is a Dangerous Thing). Unfortunately, the hype of cell therapies has led to unscrupulous players joining the field, offering unproven therapies to desperate patients. Clearly, we need thorough and rigorous regulation because, in developing immunotherapies, we are ultimately playing with the very nature of our cells. At Zelluna, we have endorsed the FDA’s position on the rigorous scrutiny of all cell therapies. In supporting the work of such organizations, we hope to contribute to the global effort to restore the public’s trust in pharma and ensure that only the best – and safest – therapeutics reach patients.
A Little Knowledge is a Dangerous Thing
The Internet and other readily available resources present patients with the opportunity to learn more about their medical conditions, empowering them to actively participate in decisions made about their own health. But with this newly found empowerment comes new responsibilities for pharmaceutical companies.
The information patients come across on the Internet or social media is not always pertinent to their specific conditions – and, depending on the source of the information, may not always be reliable. The consumption of information can often do more harm than good if it creates skewed perceptions about what therapies are truly available for a patient to use. Managing the flow of information surrounding particular products is, therefore, essential to protecting patients and preventing them from developing a distrust of the industry. Many cancer patients, for example, were of the belief that they could be cured by taking Kymriah, not realizing that the medication was only approved for use in patients suffering from B-cell acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. As an industry and as individuals, we have a duty to ensure that we do not instil a sense of false hope in patients. While the success of Kymriah was significant, it has only been dampened by allowing misconceptions about it to penetrate public opinion.
Information platforms today can also be used for the discussion of unproven therapies – a huge danger to patients. Global organizations like the International Society of Cellular Therapy (ISCT) have taken a clear stance against the use of unproven cell therapies and the society’s Presidential Task Force on the Use of Unproven and/or Unethical Cell and Gene Therapy has entered into dialogue with the FDA and is fighting to make interventions against unproven products and share effective strategies within the pharma industry.
Patients often do not distinguish between someone dying from an unproven therapy and someone dying from a proven therapy; and if this continues, we could reach a point where patients do not want to access real treatment. The industry must take a stand against unproven therapies to protect patients and the integrity of real medicines.
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