New pharmacological treatments: targeting some causes

Very few people were expecting ever to see pharmaco industry turning toward addressing the actual causes of degenerative diseases. The entire system, from pharmacological plants to practicing doctors, is based on suppression of symptoms by drugs and/or surgery. It is simply what makes more, or much more money than the typical alternative treatment, focused mainly on helping the body to regain health by relatively inexpensive means, from dietary and lifestyle changes to the use of active, generally natural noninvasive substances.

But the recent turn in pharmacological treatments for some diseases toward addressing some of their causes - although still far from complete - shows that such direction is quite possible, as long as it secures the ultimate goal: big profits.

So, we are witnessing the arrival of new, expensive and super-expensive drugs or, rather, very complex pieces of bioengineering, for treating diseases like spinal muscular atrophy (SMA), and cancer.

The $2.1million drug

With SMA, it started as recently as 2017, with the approval of Spinraza (Biogen, Cambridge MA), followed by 2019 approval of Zolgensma (Novartis, Switzerland), and soon likely to include Hoffmann-La Roche's risdiplam (still in experimental phase).

Spinraza works by changing the SMN2, gene secondary to SMN1 gene (missing or non-functional in individuals with SMA), to produce more of the SMN protein complex, necessary for motor neurons in the spinal cord to function. Without them, muscular atrophy, debilitating and possibly life-threatening disease, takes place.

Risdiplam also works by modulating SMN2 gene.

Unlike them, Zolgensma replaces the primary, SMN1 gene function by infusing into the body copies of the gene enclosed into a virus-carrier (or vector). It remains out of the motor neuron cell's DNA, but does tell to the cell to produce SMN proteins needed for its existence and signaling function.

Both, Spinraza and Zolgensma have

numerous possible side-effects,

from headache, bleeding and vomiting to serious liver or kidney injury, including potentially fatal kidney inflammation. It doesn't make it any better that the manufacturers seem to be not fully forthcoming with respect to disclosure of some problematic data: this last summer the U.S. Food and Drug Administration threatened possible criminal or civil charges against AveXis, Novartis' U.S. biotechnology unit, for manipulation of early data on Zolgensma (implicated scientists were since replaced).

So the picture is not exactly rosy, but it did not prevent the drugs to hit high sales marks: only in the 4th quarter 2019, Spinraza reached $546 million, and Zolgensma $186 million. Not surprising, considering that the former goes for $750.000 for the first year of treatment ($375.000 annually thereafter), and Zolgensma's one-time cost is about $2.1 million per patient. Which makes it the highest drug price tag in the world.

However, Spinraza treatment is more expensive, especially when it comes to the cost per life-years gained. While the overall treatment cost is similar, Zolgensma is more effective. Measured by cost per life-years gained, it is about three times less expensive than Spinraza (The Effectiveness and Value of Treatments for Spinal Muscular Atrophy, Pearson et al. 2019).

Taming cancer with immunomodulation and gene therapy

For quite a while, it seemed as if conventional cancer treatments, chemo, radiation and surgery, are cast in stone as the only option official medicine has, or care to offer. Knowing that the three were gradually introduced during 1950s and 60s as cancer treatments, we are talking about half a century of sticking to this kind of highly invasive treatments that were attacking the end product of body's malfunction,

without any regard to a number of internal and external factors causing it.

It obviously could only have a very limited effectiveness. Still, it was definitely a step ahead from drilling a hole in the skull in order to let the evil spirit come out which, as some evidence points to, was how they treated head-related disorders back in the cavemen day. Most importantly, it was very profitable.

It was the 1990s that saw the first attempts to move toward more sophisticated treatments, addressing at least the mechanisms of cancer growth, although still leaving out its environmental causes. These attempts moved along two main directions: helping the immune system fight cancer more effectively (immunomodulation), or changing faulty genes, contributing to, or fueling cancer growth.

Immunomodulation targets various aspects of the immune response, from enhancing activity of the killer cells, to marking cancerous cells with antibodies for destruction by the killer cells, or infusing cytokines, small proteins that are naturally part of the immune response and generally make it more efficient.

As for the gene therapy, there is a number of cancer-promoting genes, so called oncogenes, implicated, including KRAS (or K-RAS), TP53, BRCA1, BRCA2 and others. Most often there are multiple oncogenes involved.

Other treatment options were also experimented with. Notable example is a special photosensitive agent absorbed selectively by the tumor, used in combination with LED light, or laser, which chemically activates the agent,

turning it into a tumor killer.

Dr. Harry Whelan had several successful procedures of this type (it isn't surgery, since there is nothing that is being cut, or inserted), including complicated brain tumors. The biggest disadvantage of this treatment seems to be its low price.

Among recent developments is a DNA nano-robot, which can be designed to correct genetic malfunctions. For instance, nano-robot intended to correct particular KRAS gene malfunction is made of DNA fragments, so that it has the ability to exert corrective action on the gene's faulty RNA, which causes it to malfunction and fuel cancer growth. Such nano-robot costs little to create, but it is yet to be worked out how to deliver it to the gene.

Nano-robots have numerous possible applications other than for cancer treatment.

In conclusion, the new century is bringing better, more efficient and less invasive medical treatments for some dreaded diseases, addressing at least in part their causes. However, it is not to expect significant changes in the overall picture any time soon. As long as the primary criterion for treatment eligibility is the profit made with it, the actual internal and external causes of degenerative diseases will be taking the back seat to treating the symptoms.

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