Why gene therapy flopped and DNA vaccines were hatched to fill the blockbuster gap
Big Pharma had run out of options
Find It, File It, Flog It has not been good for Big Pharma
Some of you may recall what I’ve dubbed the Find It, File It, Flog It business model that Big Pharma adopted in the early 1980s. This it is in mathematical terms:
F1 + F2 + F3 = $$$, where:
F1 = Drug discovery (Find it)
F2 = Regulatory approval (File it)
F3 = Sales & marketing (Flog it)
$$$ = Megabucks
…and this is the clever scientist during F1, finding it:
In reality of course, he doesn’t have a clue what he’s found—until it can be manufactured at the required scale, it doesn’t exist.
However, his boss is keen to hear good new to pass up the chain, so up it goes…and the miracle compound becomes one of the 250 compounds that must enter the development pipeline to get one approved for sale.
Having ‘found’ the compound, it moves into preclinical development. This is where it’s passed over to contract organisations, working to a fee-for-serve business model.
You may remember from previous articles, Big Pharma jettisoned the skills and facilities needed to get F2 done in the early 1980s, as mentioned above, so they are now in the hands of the people and facilities they cast off. They have grown like topsy over the years and are now giant corporations themselves—check it out below:
It includes my interview with Megan Redshaw on the topic, when she was at TrialSite News. Megan has a wonderfully relaxed style of interview :O) (note: search my name on Rumble, and you can find other interviews (eg Reiner Fuellmich).
I’m not making a judgement on the quality or performance of the companies involved in providing outsourced services to pharma. This is about the fundamental principles of business. If a company finds itself locked-in to its supply base, with no alternative provider, it is in an incredibly weak position, and can expect to be taken advantage of—shareholders will demand that. In this environment, where contractors are paid irrespective of a successful outcome for the pharma sponsor, it’s not a good thing!
Remember also that once a contractor(s) is included and accepted in the license application to market a drug, no other contractor(s) can be used.
The net result of all this is that getting drugs approved and on the market has become increasingly difficult for Big Pharma, especially after it outsourced early stage drug development to tiny companies. (eg BioNTech/Moderna).
Having failed to make any progress with mass markets such as Alzheimer's and heart conditions, attention turned to rare diseases, orphan indications and all things cancer, such as blood cancers. That’s when gene therapy steps in.
Gene therapy—not the great white hope
Gene therapy was to be the next great hope for a new generation of blockbusters flowing from Big Pharma pipelines. Reality has been very different, however, as we will now discover.
One of the early gene therapy candidates is described in the Pharmaphorum article Glybera, the most expensive drug in the world, to be withdrawn after commercial flop. The article states:
“The single dose treatment broke all records with its price, costing over 1 million euro ($1.2m) per patient.
However open label studies of the drug have found that one of the key efficacy measures, reduction in pancreas disease, is only lowered by about 50%.
This and other shortcoming in the drug’s dataset have compounded concerns about its huge cost, and meant that very few patients received the treatment – some sources say the drug has only been paid for and used commercially once since its launch in 2012.”
This is one of the big issues with gene therapy—the patient population is so small that the price tag is unaffordable for health care systems.
Room for optimism?
Optimism began to return to the industry when the first gene therapy product was approved for use in the US. The treatment is known as CAR T, for use in rare blood cancers. The product is marketed by Novartis under the trade name Kymriah.
For Kymriah, the news is not brilliant either. As well as the price tag for the drug itself ($475,000 when launched), the hospital must bear similar costs to extract patient cells and reinfuse when received back from the manufacturing plant carrying out the genetic modification of the cells. The manufacture typically takes between 2 to 6 weeks. In that time, some of the patients are too weak to survive the wait. Others could be subject to cytokine release syndrome or neurological toxicities listed on the product website and packaging.
Much more room for pessimism
That optimism was preceded by a period of Big Pharma companies paying top dollar to buy small companies operating in the CAR T space:
Bluebird Bio Has Serious Cash Flow Concerns; Inability To Strike Reimbursement Deals In Europe Partly To Blame
In summary, they spent an eye watering amount of cash purchasing apparent rising stars, dabbled in a bit of patent wars, but nothing has come of it.
The Great White Hope has become the gigantic white elephant.
What are the reasons for the failures?
CAR T therapies have been the vanguard of gene therapy, being classed as ‘autologous’ therapies (oh-tol-o-gus). This means they are specific to the patient, adding a whole new layer of complexity to the supply chain. This is the traditional supply chain flow, from source materials to pharmacies and patients:
With autologous therapies, we have a circular supply chain, as shown below:
(note: sponsor company = company running the clinical trials)
It begins with the patient in a hospital or clinic, having some of their cells removed (apherisis) and prepared to send off to the manufacturing plant. They must be stored and shipped in what are known as ‘dry shippers’, containing liquid nitrogen. Dry shippers are designed so that the liquid nitrogen does not spill out. At -195°C, you wouldn’t want that dripping onto your foot!
Remember also that the patient is the source of starting material, and the destination for the manufactured, finished product. That is a major barrier for gene therapy products, as traditionally finished products go through the wholesale distribution network to get to hospitals (see above).
Barrier #2 is that the lot (or batch) size is a single unit, whereas manufacturing plants are set up to manufacture thousands, and even millions of units. Big is not beautiful in this case.
Barrier #3 is that manufacture must be carried out under good manufacturing practice (GMP) and storage and transportation must be carried out to good distribution practice (GDP). This means there must be multiple quality checks along the circular journey, when the manufacturing plant is likely 200+ miles away. Any mix up, such as the wrong cells being administered to the patient, is certain death. Is that risky enough for you?
Barrier #4 is to do with gene therapy products being biologic in nature—they are ginormous molecules (aka large) and can wither and die if not kept in the manner to which they are accustomed. That means the environments they experience during storage, processing and transportation, must be carefully controlled, especially in relation to temperature conditions. Biologics can be lost in the blink of an eye. A moment’s failure in concentration, from an operator or material handler, can mean months of work wasted. A temperature data logger not properly validated, activated, or downloaded can yield the same result; valuable product in the bin.
Barrier #5 is that even seemingly minor alterations in a process, or processes, can change the product, with potentially devastating effect. This has led to the mantra in biologics that “the process is the product.” The molecules are so large and complex that it is often impossible to define their molecular structures by analysis. All that is known is that a particular process has produced something that has a certain biological effect on a patient. A different process is likely to produce a product with a different clinical effect. Without clinical trials, that cannot be known.
There were no clinical trials testing ‘jab’ bioequivalence during SARS-CoV-2 injection development.
Barrier #5 is that input materials can also be problematic. They can dramatically affect yield, potency, and quality of output, as the strength (titre) of each new supply of materials can vary widely, depending on factors that are not always obvious to the acquiring company. Getting good pedigree information from suppliers, especially when the upstream supply chain leads to seemingly anonymous donors, can be a nightmare, and sometimes even impossible.
Barrier #6 is the cost of goods. When it’s all added up, COGS can often make a promising compound commercially nonviable and lead to catastrophic outcomes for the sponsoring company.
The Pharma Supply Chain was founded on Small Molecule Drugs
Having heard about the barriers, the following is not good news. The foundations for the pharma supply chain were set in an era where small molecule drugs predominated. Unfortunately, there was no re-engineering to cope properly with biologics when they arrived on the scene; they were basically shoehorned into what already existed.
One of the outcomes of this is that biologics have never been an easy fit in the world of the pharma supply chain. The relative predictability of the ‘one-size-fits-all’ small molecule supply chain meant that biologics had to have special treatment. The chain of custody still relies on ‘babysitting’ the product and materials through the various storage and transportation steps. Even then, it is hard to keep a handle on all the various regulatory compliance issues that exist and the protective measures needed to be taken to counter them.
Gene Therapy Arrives on the Scene
In the Kymriah case, we know the treatment IS patient-specific (autologous). These are often termed vein-to-vein supply chains, and we now know this is where a patient’s own cells are removed, genetically modified, and then re-introduced into the patient.
Reading the above, hopefully you have learnt that gene therapy represents a step change in the supply chain challenge. The shelf life of materials can be measured in hours and days, not the two years plus in the world of chemical drugs. Temperature excursions are a constant threat to product integrity, in contrast to the ‘store below +25°C’ as is prevalent in the small molecule world. For biologics, if excursions occur, it is often impossible to detect the impact on quality.
Regulations are in their infancy, as are most of the clinical trials running at this present time. Relative immaturity of manufacturing processes makes for the kind of uncertainty that can bring supply chains to their knees.
This is where the desperation kicked in
I hope to have convinced you that gene therapy products never had a future in the real world of producing safe, effective products for customer markets. However, that didn’t stop the heavy investments that have gone into gene therapy across Big Pharma and its contractors and other service providers, and hangers on.
Faced with another massive failure, SARS-CoV-2 injections were hatched.
Here is the UK, the Government got right behind it, in an attempt to lead the world in pharma R&D in a post-Brexit world. Read more here:
In the article, we see the vast array of ‘stakeholders’ all with their fingers in the gene therapy pie. Scroll down and I’ll meet you further along:
Academic Health Science Networks
Academy of Medical Science
Accelerated Access Collaborative
Ada Lovelace Institute
Advanced Medical Solutions
Alzheimer’s Research UK
Association of British HealthTech Industries
Association of the British Pharmaceutical Industry
Association of Medical Charities
British Generic Manufacturers Association
British Heart Foundation
British In Vitro Diagnostics Association
British Heart Foundation
British Lung Foundation
Cancer Research UK
Care Quality Commission
Chief Scientist Office – Scotland
Dementia Industry Group
Department for the Economy –
Health Data Research UK
Health Research Authority
Human Fertilisation and Embryology Authority
Human Research Authority
Human Tissue Authority
Imperial College London
Invest Northern Ireland
Johnson & Johnson
Medicines and Healthcare products Regulatory Agency
Medical Research Council
National Health Service England
NHS Digital and NHS Digitrials
National Institute for Health and Care
National Institute for Health Research
Nuffield Department of Population Health
Our Future Health
Professional Standards Authority
Sustainable Medicines Partnership
SV Health Investors
UK Dementia Research Institute
UK Research & Innovation
Understanding Patient Data
University College London
University of Birmingham
University of Liverpool
3D Life Prints
Smith & Nephew
Quite a list, eh?! All hoping to grow their organisations, and their incomes, on the back of DNA vaccines, both mRNA and adenovirus.
What can we do about it, given the chance?
Over the last 40 or so years, far too much attention has been paid to generating clinical data to meet the next clinical endpoint, to the detriment of the supply chain.
This lack of attention has resulted in supply chains that look something like a spaghetti, explained here:
The overall message is that pharmaceutical supply chains, as they are constructed and managed during product development, result in poorly performing, even dangerous supply chains. SARS-CoV-2 injections have been the ultimate continuation of a downward spiral that has led to the complete abandonment of good (that means at least safe) working practices.
It wasn’t always like this
When today’s drug companies were in their infancies, probably in the 1950s, things were very different.
GlaxoSmithKline (then Glaxo) started by making powdered milk for babies. Beecham’s (now GlaxoSmithKline) was famous for its flu powders, Johnson & Johnson was famous for baby hair shampoo, and Novartis wasn’t even a twinkle in its grandfather’s eye.
Blockbusters hadn’t been invented, and Big Pharma companies generally had clear views of the customer constituencies they were serving. All had an underpinning focus on the need to satisfy patients first.
The words of George W. Merck, the founder of Merck & Co, provides evidence: “We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been!”
During my early days at Bayer manufacturing in Wales, the manufacturing and supply process was pretty much integrated, from the point where raw materials arrived at the back door and the finished product was made and sent directly to customers—hospitals, Pharmacies, and sometimes patients—in the home market and to other Bayer entities around the globe.
Those Bayer entities had local presence and distribution capabilities in their own home markets. Links with customers were direct, and the staff at Bayer, the company holding the license to sell the products, could handle customer complaints.
The staff making Alka Seltzer for Europe had a standing joke. A polystyrene packing piece was at the top of each glass bottle as a cushion to prevent the tablets from moving and breaking. It was a frequent occurrence for customers to send the piece back to the plant with a complaint that it wouldn’t dissolve.
The reply was always polite and understanding, but it was hard to resist a wry smile.
What about some ideas?
I’ve been sharing ideas for years now, based on a move back to the days of old, when the industry was fully integrated and pharma companies owned the skills and facilities required to bring drugs to market.
As it happens, Shabnam Palesa Mohamed interviewed me for Good Morning CHD September 1 this year, where I had the opportunity to air my thoughts:
That should get you thinking! (I’m on first)
Finally, this goes back to 2017, and before
Some of the content here is taken from an article that I had published in Clinical Trial Arena, in 2017, titled: Advanced Therapies: Patient-Centric Heaven or Supply Chain Hell?
On top of that, I’ve reworded other stuff published at various times since 2011.
Is there hope for the future, in spite of the SARS-CoV-2 injection fiasco trashing all safeguards in the industry?
Mother Nature always wins in the end, no matter how clever perpetrators thought they were. She always gets the last word.
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