A Platform for Progress

Exemplary clinical results for patients with severe diseases herald cell and gene therapies as an answer where treatment options have not been available with other treatment modalities. Many more unmet needs remain, but getting new trials off the ground – or even submitting an investigational new drug (IND) application – can be challenging.

Here, Ian Gaudet, Chief Scientific Director for Miltenyi Bioindustry, Miltenyi Biotec’s CDMO services, discusses the issues that are slowing drug developers down and explores what approaches can accelerate their mission.

What is the main obstacle in the cell and gene space?
 

In a word: access. There is still a huge mismatch between the number of patients who need these therapies and the ability to create them in a timely manner. There is clearly work to do to make these therapies easier to manufacture, but we are also seeing many great ideas being proposed by the research community, including new targets, new approaches to CAR T cells, and new constructs. We cannot ignore that the global macroeconomic situation is tough; the funding needed to get innovations into the clinic is extremely hard to come by. Many developers are simply unable to afford the time and costs necessary to generate the data that will allow further investment.

What about in the regulatory landscape?
 

The last few years have seen a concerted effort by regulatory agencies to generate guidance documents that are specific to cell and gene therapy. In the past, one of the challenges in achieving IND approval was the lack of specific guidance. Everyone had to figure out how to build regulatory submissions based on information crafted for other modalities.

Developers will be able to move more rapidly now that regulators are invested in the space. One recent FDA draft guidance document [https://bit.ly/4fAAWdR] explains how platform technologies can be used to accelerate clinical and commercial development for cell and gene therapies. If developers can leverage existing platforms with regulatory precedent, it will reduce the work required to get a phase I trial started.

What exactly does “Platform CMC” mean – and what are the benefits? 
 

One major challenge with getting a new trial started is the IND submission and the data that needs to be included. Platform CMC (chemistry, manufacturing, and controls) essentially minimizes the de novo work needed to demonstrate safety, as well as control of the manufacturing process. But it is a new concept for cell and gene therapy. In other modalities, there is greater adoption of the platform CMC approach because there are sufficient existing regulatory submissions that new therapies can leverage or “piggyback” onto from a regulatory perspective.

The cell therapy space has less precedent to leverage such approaches, but we’re seeing a shift in that mentality given the number of commercially approved products and technologies. If we can bring all the clinical and commercial success “pieces” together into a bigger picture, it will be easier for customers to leverage what has already been filed. The upside? Much more cost-effective and rapid approval of early phase therapies.

How does Miltenyi Biotec support customers with (platform) CMC?
 

Most new therapies in development fail. Helping customers get to phase I faster, find a successful asset faster, and fail faster on assets that don’t have a commercial future – preferably without having to spend multiple millions of dollars and several years getting that trial started – is key.

At Miltenyi Bioindustry, we are developing end-to-end CMC support – or platform CMC – to help enable a paradigm shift in how cell and gene therapies are brought to the clinic. Developers need to show regulators that their viral vector is manufactured in a safe and consistent manner and demonstrate that the vector can be successfully integrated with the cell source and manufactured into the final product in a controlled manner.

Miltenyi Bioindustry has a number of components that can expedite the journey to an IND-enabling data package. For customers using a Miltenyi Bioindustry lentiviral vector,master file support enables them to use the vectors in a clinical trial with minimal additional development or CMC work required; after all, the FDA has seen our vectors many times! We would also like to expand upon this approach to include not just the vector, but the cell manufacturing, testing, and release to enable developers to simply point to a master file package and have the FDA (hopefully) accept IND submissions in a much more rapid fashion.

In fact, Miltenyi Bioindustry offers master file support for many manufacturing technologies, as well as our consumables, reagents, and software. Now, our focus is on augmenting master files or generating new master files that include analytical technologies, manufacturing workflows, and facility designs to support significant improvement in the time and effort needed to achieve approval.

Are you essentially talking about a plug and play approach?
 

Yes and no. The term “plug and play” is often used as a buzzword in the industry and typically refers to technologies that are fit for purpose for manufacturing and characterization; however, the onus is often on the developer to demonstrate that those technologies are, indeed, fit for purpose in their IND application – and that is time consuming. Today, we have a sufficient body of data on how CAR Ts are produced, so there is no good reason why we need to keep doing the same work for every new therapy – particularly when developers are leveraging manufacturing platforms that have regulatory precedent. And that’s what Miltenyi Bioindustry offers. In this case, the term “plug and play” is properly fulfilled!

What are the dangers facing developers who are not moving fast enough?
 

Companies won’t be able to survive financially if they cannot generate enough clinical data to get more funding. Current expectations from the investment community are high, with good clinical data being a prerequisite to receiving the next rounds of funding. If customers are delayed – in getting an IND, for example – they may fall at an unexpectedly early hurdle.

The technical and biological risks have always been present in R&D, but today’s focus on speed to clinical data is a real danger for new developers – even with good assets that have clinical promise.

What sets Miltenyi Biotec’s solutions apart from its competitors?
 

Miltenyi Biotec occupies a genuinely unique position. A customer using our manufacturing technologies, our analytical technologies, and our regulatory precedent will benefit from a true platform approach.

Usually, companies will use a collection of different components from different suppliers: vector from supplier A; manufacturing technology from supplier B; bespoke analytics from a collection of other manufacturers, all wrapped up together at a CMO and used to generate a data package. Customers that work with Miltenyi Bioindustry can obtain everything needed to produce a CAR T, including the raw materials, production equipment, knowhow, and regulatory support.

It seems like platform CMC could usher in a new era in advanced therapeutics…
 

By giving start-ups and academic groups with limited funding an easier path to get therapies into the clinic – I would strongly agree with this statement. A true platform-based CMC approach could be a paradigm shift for early stage developers whose new and exciting therapy may otherwise not see the light of day.

The current economic environment has undoubtedly affected innovation. There is much less funding available, as well as tighter scrutiny on what gets funded. For those developers that want their therapy to show clinical promise, working with Miltenyi Biotec gives them access to a platform CMC approach in a truly “plug and play” fashion. All that is needed is the transgene of interest – and we can take care of the rest.

The best approach to accelerating progress is to remove unnecessary time and hard work from the equation. We can do this by using what we’ve already invested in for the vector, manufacturing platform, reagents, and manufacturing milieu to allow new developers to do less work, spend less money, and generate IND enabling data packages in less time.

Platform CMC is an enabling technology that Miltenyi Biotec will rely upon to refine guidance, provide expertise, and enable a standard approach to cell and gene therapy development.