Commercializing Cell-based Regenerative Medicines

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When introducing a regenerative medicine cell based product to a commercial setting, there are a number of things to take into consideration to ensure a commercially viable and safe product for patient use.

In this QandA interview by Pharma IQ, William Fodor, Director of Translational Sciences, Cell Therapy Group, gives a few insights into the commercial manufacturing scale‐up process of cell therapies.

Listen to the podcast here (registration required) or read the transcript below:

Pharma IQ: Can you give some advice on the best way for a company to develop standards for commercialization to improve safety?

W Fodor: As with any biological product, you have to do all the appropriate testing and there’s really no standards necessarily to be developed by the company because the regulatory process is pretty well outlined by the FDA and CBER. Cell therapy products are regulated by the office of Cell Tissue and Gene Therapy Division. So, it’s not that you need to develop standards for commercialization you just need to follow the regulations by demonstrating to the FDA that your product is safe, and maintains the identity, in other words, your product doesn’t change during your regular manufacturing process. Purity and potency are all assays that need to be developed within the manufacturing process for your particular cellular product.

Pharma IQ: And what are some approval processes and pitfalls to be aware of within the scale-up process?

W Fodor: As you are scaling up your process to meet clinical trial requirements and eventually commercialization, you absolutely need to maintain current good manufacturing practices, cGMP.  Typically, during a phase one, you can get away with certain reagents that may not be fully GMPs. Or in other words, if you use a growth factor or a certain media that doesn’t have or isn’t manufactured under full GMPs, as long as you test that particular reagent or media that you are using to ensure safety and sterility, you can typically get away with that in the phase one clinical trial process. But when you move to a phase two, you need to make sure that all your reagents and medias and any compounds that come in contact with your product are all manufactured under cGMP.

Pharma IQ: What are some technology transfer and patent protection concerns to be cognizant of?

W Fodor: With any cellular-based product, if there’s a technology that is out there that a company wishes to pursue, to improve yield, or the manufacturing process, you need to demonstrate that that technology fits within your manufacturing process. So typically, what is done is you’ll do validation runs to ensure that that new technology satisfies the regulatory process for your manufactured product.

With respect to patent protection, again, that company needs to maintain their IP portfolio and needs to make sure that they’re not infringing other intellectual property and that’s just standard for the industry.

Pharma IQ: And do you have any tips for ensuring quality and consistency no matter how little or how much one is producing?

W Fodor: Yes, when you manufacture a cell-based product, it’s not that much different than any other biologic product. And so, during your  manufacturing runs, whatever scale it is, you have to ensure safety, such as sterility tests for microplasma, or other adventitious agents; as well as bioburden and endotoxin.  These are all tests that  need to be performed.

You need to have an identity test to make sure that your cell product, at whatever scale you are manufacturing, that at the end of that manufacturing run, the product hasn’t changed. Again, no matter what scale you’re at, you need to make sure the identity of the product is consistent from batch to batch.

For identity, you can do a number of things for a cell-based product, if you want to look at cell surface antigens to ensure that the cell surface proteins on your cellular product don’t change over time or through your manufacturing process. And typically, what you like to do is keep it relatively simple. You don’t want to test for a hundred things because you’re just asking for the potential for something within those hundred tings to change. So typically, what you do is maybe three to four cell surface antigens to ensure your product identity is consistent. You can also run PCR tests to determine that an intracellular protein of interest doesn’t change during your manufacturing process.

You also need to ensure for purity, so you want to quantify the purity of your active cell type or your tissue type. And then potency; you need to demonstrate the product has a consistent potency and the biological activity of that final product doesn’t change during the manufacturing process.

And then typically, what you do is you archive. You archive samples from your manufacturing process. You cryopreserve those so you can always go back to ensure that that a particular batch was consistent with other batches that were manufactured.

To contact Bill for any follow-up or other questions related to cell therapies, see his contact information on the Cell Therapy Group website.

For a PDF copy of this interview, click here to download.

Good Data? $100. Good Product Development? $100. Good Commercialization Strategy? Priceless.

I'm not going to fool anyone into believing I'm a therapeutic product development expert but that's not going to stop me from making a few humble observations in light of the Dendreon "fiasco" of last week which I have no doubt will one day be considered an unfortunate pothole on their road to eventual success.

(though perhaps not before certain current management finds themselves polishing their CVs or retiring to spend their time alternating between their yachts and the courtroom defending their questionable stock trading antics)

I received the following message this morning by email. I don't include it here to promote or endorse or even comment on NWBT, DCVax, Linda Powers, or Toucan Capital in any way -- or in a way that is blind to all the things right or wrong about any of them -- but simply to illustrate the 3 points I want to make below the email.

NWBT HIGHLIGHTS COST EFFECTIVENESS OF DCVAX® IN VIEW OF RECENT IMMUNOTHERAPY PRICING CONCERNS

Northwest Biotherapeutics' (OTC.BB: NWBO)... DCVax® immune therapies for a broad range of cancers (including prostate, brain, ovarian and others) hold the promise, based on available data to date, of being cost effective and priced below other immune therapies while still providing substantial profit margins for the Company and longer survival for patients.

The investor concerns in the news relate to the pricing and reimbursement of Provenge for late stage, metastatic prostate cancer. Provenge is priced at $93,000 for one month of treatment and was approved by the FDA based upon having added 4.5 months of patient survival (to reach overall survival of 25.9 months).

NWBT’s DCVax® will be priced in the range of $37,000 per year for up to 3 years of treatments. In NWBT’s Phase I/II multi-center clinical trial in late stage, metastatic prostate cancer, DCVax® added 18 months of patient survival (to reach overall survival of 38.7 months). DCVax® has previously been cleared by the FDA for a 612-patient, randomized, controlled Phase III trial, although the trial has not yet begun. As is typical before a Phase III trial, the manufacturing processes and product costs have already been determined.

...

...

The key to the substantial pricing advantage of DCVax® is NWBT’s proprietary batch manufacturing process together with its cryopreservation technology for frozen storage of the finished vaccine. NWBT has spent a decade developing and improving its manufacturing and cryopreservation processes. The manufacturing of personalized, living cell products is expensive. But the frozen storage of living cells is quite low-cost – once the specialized freezing technology is worked out for a particular type of cells (the culture conditions, rate of freezing, density of cells and many other factors).

NWBT’s manufacturing methods produce – in a single manufacturing run – a large batch of personalized DCVax® product for 3 years of treatments are much less costly than separate manufacturing runs for each treatment. The technology for freezing the master immune cells (dendritic cells) which comprise DCVax® enables these

cells to remain frozen for years and, when needed, to be thawed and “come back to life” with full potency.

This approach makes DCVax® an "off the shelf” product [for that patient] for several years of treatments after just one manufacturing run. In contrast, Dendreon must do a separate manufacturing run for each one month of treatments. In addition, Dendreon's Provenge product is fresh and not cryopreserved, which limits its shelf life to at most a few weeks.

Another important factor in the cost effectiveness of DCVax® is its simplicity and ease of administration. DCVax® is delivered as a small intra-dermal injection under the skin, similar to a flu shot. As such, it can be administered in any physician’s office or clinic. There is no lengthy intravenous infusion, with the attendant patient discomfort, cost and need for a specialty infusion center. In contrast, Dendreon’s Provenge is delivered by intravenous infusion.

The cost effectiveness of NWBT’s DCVax® is enhanced by the fact that DCVax® is targeting a portion of the prostate cancer market that is 4 times the size of the market segment that Dendreon’s Provenge is currently targeting....

Now this is NWBT clearly blowing their horn - nothing wrong with that - in an attempt to woo back frightened investors. I'm agnostic as to whether any of it is true but it does serve to draw out several points of distinction between what some companies might do to optimize their products for commercial success versus what others might do in an overriding belief that clinical benefit is the only precursor to the happiness of investors, the physician community, patients, and partners.

What I say below is not a commentary, in criticism or praise, on any particular company including NWBT or Dendreon. Many others - Luke Timmerman among the best of them - have provided outstanding and in-depth analysis of the Dendreon story along the way.

I'm only interested in what we as an industry might learn from recent experiences or trends and to perhaps facilitate a useful discussion based on 3 simple observations from someone who has swum in this cell therapy pond for now just over a decade:

1. There is a tendency among some to believe that what we are making (cell-based therapies) are so revolutionary and compelling that the products should almost sell themselves - to investors, partners, regulators, insurers, physicians, and patients.

Of course we know it's not true but sometime we act like it is.

Appligraf and Dermagraft didn't sell themselves to physicians even after regulatory approval. Neither is Provenge apparently-- though they did a good job of selling it to very vocal patient groups. Organogenesis and Advanced Biohealing had to work very long and hard to get profitable reimbursement and market penetration. Dendreon will too.

Investing early in understanding potential clinical adoption hurdles, reimbursement issues, and how the product is and will be perceived not by its champions but by its critics and most importantly, the average agnostic practitioner, is not easy to do because it means spending precious resources long before there is a product to sell but it may mean the difference between a product which eventually sells and one which doesn't.

2. There is a tendency to de-emphasize what I call the "ancillary sciences" around a product -- like lowering the cost of goods, optimizing fresh or frozen storage, cell delivery (e.g., injection/application science) mechanisms, in vivo cell tracking, onsite clinical handling, etc.

Product development science is a science. The science that turns good data into something commercially viable. Not everyone is good at it and certainly this is where a lot of companies fail. PD is not the 'second cousin' in the room of esteemed basic and clinical science.

Take these examples when considering the cellular immunotherapy sector:

Several prominent immunotherapy investigators I have spoken with strongly believe cell-based immunotherapies will require long-term administration to be meaningfully effective -- certainly longer than 3 doses in 3 months. Did Dendreon lock into their clinical protocol too early?

Other immunotherapy companies - like Opexa Therapeutics for instance - create multiple doses for a patient from a single patient collection thus saving considerable expense and creating a better patient experience. Did Dendreon lock into their manufacturing protocol too early?

Other companies are investing heavily in finding ways to extend viable shelf-life of their fresh products or to create cryopreserved versions of their product to optimize its commercial viability.

Imagine a Dendreon that only had to build one manufacturing facility (with a backup CMO) to serve the US market rather than 3 facilities. With a cryopreserved version of the product or a version that had longer than its current limited shelf-life (~72 hours I believe?) that might have been possible.

At every point in clinical development there must be concurrent R&D towards the product's:

1. science (e.g., MOA, characterization, etc),
2. clinical effect, and
3. how to optimize its commercial viability - a big part of which is what we think of as 'product development'.

This is the 3-legged footstool of a commercialization strategy geared for success (credit to Bob Preti of Progenitor Cell Therapy for this analogy).

But 'product development' is also not always about the product strictly speaking and even an expansive definition of product development is only part of a good commercialization strategy.

There is significant component of it that is about studying ways to lower the cost of goods, improving manufacturability and scalability, how hard/easy it is to handle, the patient treatment experience, the physician experience, how it impacts patient's QOL (quality of life), not just what side effects it generates but what side effects it prevents (resulting from other treatments or no treatment) and the cost-savings that generates, etc.

Other cell therapy companies have been more proactive in terms of engaging not only KOLs but average practitioners in a meaningful way that might impact their product and clinical design as well as reimbursement and clinical delivery issues.

3. There is an understandable, largely VC-driven, desire to race forward to the next trial phase when a phase-repeat to optimize or better understand different aspects of the product might be the better way to go.

What's worse? Facing the prospect of not being able to get funding or a partner on the terms one wants for a 2nd phase II or burning through a bunch more money in phase III in an attempt to bring a product to market that isn't market ready? I understand its a tough choice -I'm not saying it's an easy one - but one is certainly more strategic and, as pharma says, is certainly a "de-risking" pathway.

Consider the ratio of products we've seen thus far in the cell therapy industry's short life-span that have been raced to phase III or (worse yet) market only to seriously stumble if not fail when they get there. I can think of 8-10 off the top of my head and there are less than 20 cell or tissue based therapies on the market in US/EU that have received any kind of formal regulatory approval.

Some would argue that this is a prime example of why spinning companies out of academia too early is not beneficial because companies want to minimize exploratory science and lock into a "product" too early. I would argue that this may be true if the problem is understanding the product characterization or mechanism of action but not if your problem is related to how best to develop/optimize the product for commercial viability. Few academics are geared to think this way.

Summary

I certainly don't believe Dendreon failed to identify or consider each and every one of the things they might have done better along the way. I'm sure they did and sure they made calculated judgement-calls about how to approach each one.

Since I'm not a shareholder I don't have to worry myself about being critical of their decisions but rather simply to do what I can to ensure that we as an industry do our best to learn from what - with the benefit of retrospect - may be apparent they did right and wrong.

What are your thoughts? To what extent are the problems that Dendreon has experienced along the way with PROVENGE a predicable result of it being a first-generation product or the result of insufficient focus on critical investigation into the less sexy "ancillary sciences" of product and commercial optimization?

(comment below and/or in the LinkedIn Cell Therapy Industry Group)

Cell Therapy Industry HiLites 2009-01-09

Ok so there was no deluge of cell therapy news this week despite my fears (hopes?). The only flood was the river (nee creek) behind my house. Wow, water can rise fast! Anyway...that's not cell therapy, THIS is cell therapy:

Osiris Therapeutics (NASDAQ:OSIR) received a $5 million milestone payment for reaching the first production threshold of the Osteocel supply agreement with NuVasive. In July of 2008, Osiris announced the sale of the Osteocel business to NuVasive for an initial payment of $35 million, followed by up to $50 million in additional milestones. Osiris expects to achieve the remaining $45 million in milestone payments from NuVasive, including $17.5 million for further delivery of product, $12.5 million upon transfer of certain manufacturing assets, and a $15 million payment upon NuVasive’s achievement of $35 million in cumulative Osteocel sales.

After announcing last week that they had raised $1M of an anticipated $5M round of financing, International Stem Cell Corporation (OTCBB:ISCO) issued a press release to 'discuss' the recent funding. The additional funds are to be raised in four $1M tranches in February, March, June and September.

They need the additional funds to meet their goals for 2009, namely
(1) eliminating $1 million of outstanding secured debt;
(2) supporting first quarter pre-clinical trials; and
(3) providing marketing and expansion capital to position the Company`s "Lifeline" subsidiary - which makes and sells specialty cells and growth media - to the point where it will be generating profit (within two years) that they can then plow back into the company's clinical research.

I'm no corporate finance expert but this is what I read from the SEC filing behind the press releases. Andrei Semechkin, Rouslan Semechkin, and X-Master, Inc were the investors putting up the $1M to-date. By way of a "material and essential inducement for the Investors to enter into the Preferred Stock Purchase Agreement, the Company agreed to employ Rouslan Semechkin and Andrei Semechkin in accordance with the terms" of the employment agreements attached to the stock purchase agreement. Andrei is going to be paid at least $180,000 per year for the next 5 years as the company's Chief Business Officer and Rouslan is also on salary.

So, provided ISCO stays around, Andrei and Rouslan will get their $1M back over 5 years in addition to whatever benefits they may glean from their shares. This certainly seems like a nice, low - albeit not entirely without - risk arrangement. On the other hand, this could be seen as them putting their own money in first where they are asking others to follow or they may buck up more money on the subsequent tranches. However this plays out, it is another testament to the fact that in biotech, survivability is so-oft closely if not directly tied to financing creativity!

You likely won't find a press release about this one but J&J is quietly shuttering at least two of their cell therapy programs. Their autologous HIV cell therapy program and their Treg program are both on the out-licensing block after corporate decided to shut down the programs - the former after reportedly 'good' phase II data and the latter even before it went clinical. J&J is not announcing what's behind the decisions though unofficial reports are that it is not a lack of belief in cell therapies overall. Speculation is that it is primarily HQ needing to conserve spending on longer-term programs. Whatever is behind the decisions, it's a little disappointing because for a couple of years now J&J has been quietly been the largest cell therapy company in the world if one added up all their cell therapy internal programs and external investments. They may well still deserve this title but they're a little smaller this month then they were before.

So...since it was a little slow on the industry front, I'll finish with three non-business related items I found interesting this week:

WIRED has published its much-read list of top scientific breakthroughs of the past year and not only do life sciences figure prominently in the top-10 but two of them are cell therapy related. On the list: A new approach to reprogramming stem cells to avoid a tendency to become cancerous; using a bone marrow transplant from an HIV-resistant donor in Germany to eradicate the virus, pointing to gene editing as a possible cure; and using a patient's stem cells to grow a new trachea. The new trachea was number two on the hit parade and earned kudos as the greatest single breakthrough in life sciences.

Adding fuel to the 'cancer stem cell' debate, Canadian researcher Mick Bhatia, and his team, have published a letter abstract in Nature Biotechnology, on a series of tests they claim can distinguish between cancer stem cells and the good kind. Thus enabling, inter alia, the better targeting of cancer stem cells.

Cell Transplantation has become an "open access" journal from the 1st January 2009, starting with volume 18, making it available on the World Wide Web without subscription to researchers and clinicians as well the public and members of the media.

Finally, Dawn Driscoll (DCi Biotech) and I are putting on a 1/2-day course entitled Commercial Considerations for Cell-Based Therapies Feb. 24 at the Moscone Center in San Francisco immediately prior to CHI's Stem Cell Congress (part of their Molecular Medicine Tri-Conference). Let me know if you're interested.

That's cell therapy the way I saw it in this first whole week of 2009...