By Dr Udaya K Maiya, Oncologist, MBBS, MD, DNB, DCCF-Paris
Since Geron (GERN) has the dubious reputation of probably being the most discussed healthcare stock on the Internet, there is often an overload of information about the company, its single pipeline drug imetelstat, its collaboration with Janssen, a subsidiary of Johnson & Johnson (NYSE:JNJ), and its management. In all this hullabaloo, investors new to GERN may get a little confused about the basic theses behind the GERN investment. As someone who has followed Geron and GERN for more than a decade, but never invested long term, let me try and take a broad look at GERN as an investment. In order to do that, I will begin by identifying a few broad problem areas in the telomerase inhibition therapy research. In future articles, I will see how these are being addressed by Geron and Janssen.
Geron’s imetelstat is a paradigm-changing cancer therapeutic approach which inhibits Telomerase, an enzyme that protects malignant cells from destruction by extending the protective caps or telomeres on the ends of chromosomes. Telomerase is composed of the catalytic subunit telomerase reverse transcriptase (TERT) and its RNA component, TERC. Based on more than 40 years of research, this approach, if successfully implemented in the clinic, can cause a revolution in oncology, where over 85% of tumors overexpress telomerase. That means, over 85% of tumor types use the telomerase activation pathway to sustain and grow. Thus, not only is telomerase an excellent cancer biomarker, it is also an excellent therapeutic target.
But have you wondered about the other 15% of tumor types, and how they grow and spread without telomerase activation?
The problem here is that malignant genes can replicate without telomerase activation as well. There are other ways by which alternative lengthening of telomeres (ALT) can be achieved. This is not only true of the “other 15%” but it is also true of the tumor types where telomerase activation is the method of replication. In a pioneering study from a few years ago done at MD Anderson, it was observed that while “inhibiting telomerase… kills tumor cells, (IT) also triggers resistance pathways that allow cancer to survive and spread.” Thus, a telomerase inhibitor like imetelstat can cause ALT elevation (not to be confused with the liver) and also potentially lead to more highly resistant cancers after an initial period of tumor regression which may make the drug seem like it is working during clinical trials, but actually causing harm.
The MD Anderson research also found that a gene called PGC-1ß, whose expression and copy number increases in ALT-positive cells, can be targeted to weaken mitochondrial function, which enhances activity of anti-telomerase therapies. So, this could be a proper additive target for any telomerase inhibition therapy. But that is additional research that needs to be performed before imetelstat can conceivably get to the market.
The other issue is that imetelstat will of necessity always be a combo therapy. It has to be given along with chemotherapy or another cytotoxic agent or therapy because imetelstat itself is not directly cytotoxic to existing malignant cells. Its job is to prevent replication, but it can not harm cells that are already malignant. Therefore, all the other problems with cytotoxic agents will crop up in any imetelstat-based therapy scenario. Proper targeting will, as always, remain a necessity.
A related problem is that some cardiovascular side effects of known chemo drugs like doxorubicin may actually be enhanced by telomerase inhibition in situations where telomerase has a beneficial role to play in basal mitochondrial metabolism. It is understood that telomerase has a key role to play in the general health of our heart, and while specifics are still unknown, any clinical trial targeting telomerase inhibition must face the question of how telomerase inhibition may elicit “negative effects in highly-proliferative cells which need telomerase for survival.”
Side effects are also another cause of worry, as we have seen from the clinical holds that were once put on Geron’s trials, but were later fully lifted. Some of these side effects probably occur because hTERT, the humanized catalytic subunit of telomerase, or humanized telomerase reverse transcriptase, has beneficial non-nuclear roles in other healthy, somatic tissues, as we just discussed. Below is a brief overview of some of the associated side effects of various telomerase inhibiting therapies being developed.
New research shows that telomerase may have beneficial role in broad vascular biology as well. So the concern for off-target toxicity still remains. This is the main reason progress has been so slow with imetelstat - we simply do not understand telomerase as well as we should.
Another issue is that drugs like Imatinib, marketed as Gleevec, also downregulate telomerase activity, as do a number of chemotherapeutic agents. Gleevec is a TK inhibitor per se, and while it is true that imetelstat is a specialized telomerase inhibitor, that is still a kind of competition. Not only competition, but some side effects associated with Gleevec may also accrue on imetelstat because of speculation that those Gleevec AEs are telomerase related.
This is a cursory overview of some of the obstacles telomerase inhibition will face in the clinic. The object of this overview is simple - to make ourselves aware that while telomerase inhibition is perhaps one of the most promising approaches in cancer R&D, it is going to take a number of years to bear the proverbial fruit. I would, therefore, approach a GERN investment in one of two ways. First, due to the immense activity surrounding the stock, any simple catalyst makes the stock very volatile, providing a good trading option. Second, since I personally find the telomerase approach intriguing, therefore, as long as Janssen is on board, I would buy a small volume of GERN shares, put it in a box, and throw away the keys. This should be money I am happy to lose. Maybe after 10 years, I will open that box somehow, and find that all my money is gone to dust - or that it has become a treasure trove. Funny, but that’s exactly how I think of this stock.
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: Like i said, i never invested in GERN long term, but have traded it on occasion.