Notwithstanding my prior half-hearted dig at QLD and WA-based biopharma companies, one of the most underwhelming companies in the Australian life-sciences scene is right here in my own backyard – Patrys (ASX : PAB). This is a company that has had an illustrious history of underachievement, wasteful dissipation of shareholder capital and management team largesse. It remains to be seen whether the company is capable of turning the corner under James Campbell’s leadership, but even so there are plenty of fundamental issues with this company.
Back in June we were given an update on Patrys’ manufacturing progress for the PAT-SM6 product. This update fundamentally reflects the continuing struggle of the company to deliver on the technology, and there are simple reasons why. An IgM is just bloody hard to manufacture. There are a few companies that have somewhat mastered the art of the IgM production, but the main issue is that production yield for these large macromolecules will always be low. Why? Because in order for a given cell line to “pump” out an IgM it has to produce a protein that is almost six times greater in molecular weight than a “conventional” IgG, the format that is used for the vast majority of antibody drugs. This means that for a given amount of cell energy, it is going to produce about 1/6th the material and so this typically means a 6x (+) scale-up of your bioprocess to make the same amount of materials for a clinical trial. That can equal big costs, and big waste when you get it wrong.
There aren’t actually that many theoretical benefits to making an IgM and with the current level of capability in optimising antibody molecules, it would be hard to imagine a target that you couldn’t hit with a less exotic approach. Indeed, there has been some success in recombinantly “grafting” the targeting parts of an IgM onto other antibody frameworks to make more optimised (bivalent) products. There is more art than science to getting this to work, but it is possible. In this post I will not go into Patrys’ choice of production cell line (PER.C6) or the “alleged” headaches that Patrys has experienced working with its manufacturing partners, many of which have not been (as far as I am aware) fully publicly disclosed. Needless to say that manufacturing biotech products is not just about throwing a molecule over the fence at a contract manufacturer, a painful lesson that Patrys has learned at shareholder expense.Aside from an incredibly slow pace, wastefulness and fundamental technology challenges, there is something else that is wrong with Patrys. The Patrys story simply isn’t truthful. Having spent time trawling through Patrys’ publications and a few key patents, I learned something quite remarkable. I chose to focus on US patents 8,741,296 and 8,163,552 in particular, because they relate to the PAT-SM6 candidate which is, notionally (notwithstanding manufacturing glitches), the company’s lead candidate. In understanding how the IgMs were produced, I noted that the process involved making a B-cell (lymphocyte) fusion with an immortalised heteromyeloma cell line. In fact, the cell line that was used was HAB-1, a fusion or “hybrid” of murine myeloma and human lymphoma cells. The result is a karyotype (nucleus) that consists of about 50 murine and 20 human chromosomes, in other words the genetic construction of the cell is still very significantly murine – or … in common parlance … “mouse”.
Why does this matter?
Well, Patrys’ claims* that “all antibodies on the market contain non-human components, whereas Patrys’ antibodies are completely human. The greater human composition of Patrys’ products offers potential benefits in terms of a lower risk of rejection and higher potency due to a more effective ability to communicate with the other elements of the immune system (i.e., the greater the human composition, the greater the effector function of the antibody)“. Well, firstly, that statement is total bollocks – we routinely make fully human antibody drugs, either synthetically from libraries of human repertoires, or directly from patients. We also have the ability to “humanise” antibodies that come from non-human sources (most of the block buster antibody drugs on the market today are these so-called humanised monoclonal antibodies). Secondly, the “degree of human composition” has little to do with the effector functions of an antibody and a whole lot more to do with how the immune system might tolerate the presence of an antibody that is determined to be “foreign”. But again, this is mostly a solved problem.What is truly dubious about this statement, is Patrys’ “completely human” claim. To be clear, Patrys makes the cell lines that expresses each antibody by making a fusion with a heteromyeloma cell line that is genetically about 70% mouse. This means that when the proteins are assembled, it would be entirely reasonable for pieces of those IgM molecules to not be human, but in fact be mouse in origin. I did not see any evidence in either the publications or the patents of any detailed characterisation or recombinant manipulation of the resulting fusion IgMs to address this concern. The patents are silent on matters such as a the J-Chain composition which, on a probabilistic basis, could very possibly have murine sequences as it is fundamental to how the protein assembles. Either way, Patrys simply cannot make the claim that their antibodies are completely human and I would challenge the company to claim that all polypeptide chains in its molecules are fully human.
It is a “porky”**.
The bottom line is, we don’t need this company anymore. IgMs are interesting but not really at the forefront of where antibody drugs are going. There is very little reason to develop an IgM and plenty of reasons to avoid it. Notwithstanding any valiant efforts by the new CEO to try and turn the company around, my opinion is that Patrys would be better off discarding the pipeline and starting again. Although the public market appeal of a new antibody drug isn’t what it used to be, there are some very good assets around (even in Australia) that would be a hell of a lot better – and easier – to develop than the current basket of crapola. But, if we continue to just see the management team tick over (including the Chairman who – surprisingly – didn’t depart with the former CEO, and seems “eminently qualified” to be leading an early-stage biotech company) then I guess we will know that this is just another ASX gomer, destined to slowly and painfully transform shareholder capital into executive lifestyle.
Frankly, given the huge challenges Patrys has, it amazes me how James Campbell can manage to find the time to be an effective CEO and meaningfully contribute to so many other ASX boards.
He must be Superman.
*Taken from the company web site “Technology”, 3pm 3/08/2015
**Porkie = Pork Pie = “Lie” in Cockney Rhyming Slang