Hepcidin Agents Set to Improve Polycythemia Vera Care

Protagonist Therapeutics earlier this month reported positive results from its phase III VERIFY study of hepcidin mimetic rusfertide for the treatment of polycythemia vera (PV).  This marks an important milestone in bettering the care of PV patients as it showed a reduction in the need for phlebotomies that, importantly, was further accompanied by a measurable increase in quality of life. Notably, this did not come at the cost of a greater risk of developing cancer and other side effects such as fatigue that current standard of care agents suffer from.

Subsequent to the release of the VERIFY results, Ionis Pharmaceuticals licensed global rights to sapablursen to Japanese Ono Pharmaceuticals for $280M in upfront.  

Mechanism of action

Similar to synthetic peptide rusfertide, the RNaseH antisense sapablursen aims to increase hepcidin pathway activity by facilitating its  release from the liver.  This can be achieved by knocking down its negative regulator TMPRSS6.  As a master regulator of global iron uptake, storage, and dynamics in the body, hepcidin suppresses the overproduction of red blood cells (erythrocytosis) by restricting iron supply to the bone marrow.  It is the overabundance of red blood cells in circulation and subsequent viscosity that leads to an increased risk of thromboembolic events.  Night sweats, abdominal discomfort, and bone pain are some of the other consequences people with PV suffer from.

The expected life expectancy from diagnosis, typically around the age of 60, is about 20 years.  In about 10-15% of cases, PV progresses to myelofibrosis which carries a poorer prognosis.

Current standard of care

The first-line treatment for PV is ‘blood thinning’ aspirin in addition to bloodletting (phlebotomy) in a procedure that is essentially the same as when you donate blood.  The goal here is to get the fraction that red blood cell occupy in the blood to below 45%.  This is considered to reduce the risk of thromboembolism by 4 fold compared to having a hematocrit value of 45-50%.  The main side effects from phlebotomies is fatigue and general iron deficiency.

When phlebotomy is not enough, or when you are above 60, cytoreductive therapy is indicated.  The typical reason for red blood cell overproliferation in PV is an acquired mutation in the JAK2 gene (V617F)  in hematopoietic cells leading to increased cytokine signaling.  Blood cell lineages other than the erythropoetic one may also be affected.  Second-line agents (used in combination with bloodletting) aim to inhibit subsequent cellular proliferation.

Unfortunately, second-line agents are generally blunt instruments that carry a lot of safety and tolerability baggage.  

First off is hyroxyurea which is, hold on, a DNA synthesis and repair inhibitor and, unsurprisingly is recognized to cause cancer, especially non-melanoma skin cancer.  Add to this the nausea and immune dysfunctions to mention only a few of the other side effects.  I get it: small molecule and cheap, but give me a safer, alternative medicine (and since we are at it, HU is a reminder of all the widely described carcinogenic small molecule drugs and we are agonizing about genome editing agents with mutation rates well below natural sunlight). 

Next is interferon.  Anybody following the hepatitis B virus treatment field knows that this is a very poorly tolerated agent leading  to depression and flu-like symptoms causing patients to frequently stop taking the medication.

Ruxolitinib, a JAK2 inhibitor, is certainly an advance in the cytoreductive approach in PV as it targets the root cause: JAK2 activity.  This, however, also means an increase in the risk of infections (due to suppression of immune cell lineages) and, once again, non-melanoma skin cancer.  Approved for myelofibrosis already, it will be important to see whether its use in PV can also inhibit the progression to myelofibrosis.

Role of hepcidin agents

Due to the safety and tolerability issues noted above, the hepcidin pathway agents should be well positioned to grab a major share of the second-line treatment market.  In addition to not showing an increased rusfertide-related cancer risk or other major safety issues, VERIFY demonstrated that patients actually felt better on the drug.

In some patients, weekly subQ injections eliminated the need for phlebotomies altogether as more than 76.9% on the drug did not qualify for it during weeks 20-32 compared to  32.9% on placebo.  72.8% did not undergo a phlebotomy for the entirety of the primary observation period of the study (week 0-32) compared to only 21.9% on placebo.  

Importantly, the ~300 study participants could be on cytoreductive background therapy.  This may also explain that the mean number of phlebotomies during weeks 0 to 32 for those on placebo was just 1.8, i.e. in line with a regular blood donor.  Adding rusfertide reduced this to 0.5.  

 

PK/PD comparison of hepcidin agents

In addition to the difference of mimicking hepcidin versus inhibiting an inhibitor of hepcidin, another important differentiator is the PK/PD profile of the two approaches differ.  Since peptides typically do not last long in circulation, rusfertide needs to be given weekly with more than 10x differences in peak-to-trough levels.  By contrast, both the Ionis antisense (sapablursen) and Silence Therapeutics SLN124 (divesiran) RNAi TMPRSS6 knockdown agents lead to sustained 3-5 fold increases in endogenous hepcidin depending on dose and dose frequency.

In a study in PV patients, SLN124 led to a more than 10x reduction in phlebotomy frequency compared to the run-in period, although this difference may be more moderate in a placebo-controlled study similar to the Protagonist experience.  In any case, my base case is that efficacy in terms of phlebotomy frequency will turn out to be similar between the two approaches with the more sustained, physiological increase in endogenous hepcidin possibly paying dividends over the longer term.  The reduced drug administration frequency (monthly subQ likely for sapablursen, q6w currently for SLN124) would also favor the oligonucleotide options.

Ionis has been more secretive about the performance of IONS-TMPRSS6 in PV.  They did, however, disclose in an investor presentation that during the partnering process, Ono Pharmaceuticals and other competing companies got to see those data. Based on comparable hepcidin elevations in human volunteer studies, I would expect phlebotomy and other efficacy endpoints to be roughly on par with what Silence Therapeutics has seen, although the 9mg/kg cohort with SLN124 could set a new benchmark if confirmed in a larger study.

Additional Market considerations

There is considerable interest in developing next-generation PV therapeutics.  This is also illustrated by recent deal activity in the space.  In January 2024, Takeda Pharmaceuticals paid $300M upfront to Protagonist for 50:50 US co-development and co-commercialization rights and exclusive ex-US rights following the successful completion of phase II studies.  At the time, rusfertide peak sales were projected to be in the $1-2B range.

This week, another Japanese pharmaceutical company, Ono, obtained full rights to sapablursen from Ionis for $280M in upfront following full enrolment of a PV phase II study, a deal that was likely informed by the rusfertide results.  Though enhanced milestone payments compared to the Protagonist-Takeda deal may somewhat compensate for the lower upfront consideration, the deal indicates that the estimates for the market potential for the hepcidin entrants either have come down or that this market is now expected to be divided up between more players than initially envisioned.

Clearly, the US, with a patient population of 100-150,000, will be the major source of expected profits.  Similar to the hereditary angioedema (HAE) space, similar efficacy, but much better safety, tolerability, and convenience of the new HAE therapeutics have grown that into a multi-billion dollar market despite the availability of cheap alternatives like androgens and a small patient pool of at most 10,000.  

Androgens, however, are still widely used outside the US, even in wealthy countries like Singapore, and unlike HAE, PV is largely diagnosed in older people.  This means that reducing the number of annual phlebotomies by 2 will unlikely justify a $200,000 price tag.  To justify that, hepcidin pathway agents need to have robust phlebotomy-lowering activity in the absence of any other current second-line agents (remains to be seen in the full VERIFY dataset) in addition to demonstrating improved measures of well-being as was demonstrated in VERIFY.  

Disclosure: SLN124 is the core asset of Silence Therapeutics of which I currently own shares.

Artificial Intelligence for RNAi Gene Target Discovery Still Early

It’s not every day that you can see a person like chess playing legend Gary Kasparov at a biotech company’s Investors Day.  And if you did, you might wonder whether this was  some kind of stunt.

I was therefore pleasantly surprised to find that Kasparov was indeed a very fitting appearance investor event by Silence Therapeutics this week (for presentation here).  In the 80s, Kasparov apparently gained an edge over the competition by analyzing opponents’ playing habits using ‘big data’ at a time that personal computers were only about to take off.  As a former professional chess player himself, the CEO of Silence (Ali Mortazavi) therefore believes that there similarly must be ways to more efficiently take advantage of the realms of genomic data being generated to gain an edge over the pharmaceutical competition in finding attractive targets and indications for RNAi gene silencing.

Herd mentality

One of the main reasons I used to look down at Big Pharma  with disdain was their herd mentality especially with regard to the targets and indications they are pursuing.  You can bet that if there is general hype around a certain target, or that once a target has been validated for a commercially attractive indication in a clinical proof-of-concept study, almost all Big Pharma companies will be pursuing corresponding programs.

Unfortunately, such herd mentality is not restricted to Big Pharma, but can also be observed in the biotech space (see PD/PD-L1 for cancer etc etc), even in the subsector dearest to my heart: oligonucleotide therapeutics.  Be it TTR, AAT, DMD, or HBV: once there is a compelling therapeutic rationale for pursuing a gene target, multiple companies will be on its case.

It is for this reason, particularly the fear that an Alnylam or Ionis will scorch the earth around these targets, that many companies now delay disclosing the nature of their most promising preclinical programs.  This is remarkable since small biotechs like Dicerna typically rely on disclosure of their of these programs to garner the necessary investor interest.

Target scarcity?

The fact that the lead programs of RNAi therapeutics companies frequently overlap also beckons the question of whether there is a biological scarcity of targets available.  This would be in contrast to Alnylam which have limited themselves to GalNAc-RNAi trigger conjugates for gene knockdown in the liver, claiming- in the flowery languish of its CEO- to be ‘drinking from a firehose of opportunities’ in just the hepatocyte.

To Alnylam’s credit, it has not only duplicated some of the programs initiated by antisense competitor Ionis Pharmaceuticals and that of its smaller RNAi competitors, they have done some of the heavy lifting themselves.  It was e.g. Alnylam that realized the true value of going after transthyretin for TTR amyloidosis and it was Alnylam that selected a target as unorthodox, but promising as antithrombin for the treatment of a protein deficiency: hemophilia (à ALN-AT3/Fitusiran). 

Other companies like Dicerna and Arrowhead Research can also be complimented for unearthing gene target nuggets for orphan indications like primary hyperoxaluria and liver disease due to certain mutations underlying alpha-1-antitrypsin disease.

Mining for targets

I am not concerned about a dearth of suitable targets that could inhibit the continued growth of RNAi Therapeutics.  This is because there are thousands of rare and severe diseases for which there should be straight-forward genetic solutions and because genetic/genomic information continues to explode.  Still, there is certainly tremendous value if you are the first to gain high conviction around a new target and it was the CEO of Silence who bemoaned what seemed to him like an archaic, manual process of sifting through the genetic ideas one by one.

The panel discussion largely cautioned that human curation will remain dominant for the foreseeable future.  I am slightly more optimistic (or pessimistic, depending on your attitude towards AI) and give AI 5 years or so until it will become a more and more compelling means for driving gene target discovery.  This delay relative to areas like the internet is largely explained by the fact that whereas genomic information has exploded, databases that link them to careful, systematic medical phenotyping are still in their infancy. 

In the meantime, some low-hanging fodder for oligonucleotide drug development may come as a by-product of genetically diagnosing rare diseases when often the last hope for getting a grip on a condition is to genome sequence the patient.

There are beneficiaries already from the recognition of the importance of pairing phenotype with genotype databases such as 23andMe which is said to be getting quite a bit interest from pharmaceutical companies and investors. This comes after the pioneer of sifting through genomic/phenomic data for target discovery, deCODE of Iceland, was acquired by Amgen in 2012.  deCODE rose to fame by linking population-wide genetic information to national health-record databases.  I would think that we will see quite a few more similar endeavors linking existing (à nations with a high level of social bureaucracy such as the Nordic countries) or IT-driven newly generated (à Google, wearables) health records to genome and transcriptome databases. 

And as these databases grow and become more intelligent, it will be those that first understand to harness them that will gain a Kasparov-style edge over the competition.  But don’t be afraid: AI should not make human gene target discoverers/evaluators redundant any time soon and their cost relative to the cost of developing drugs is too low.  If anything, they will be needed to make the ultimate decision of whether to pursue a proposed target as each disease is unique and it will take a long time until enough billion-$ clinical experiments will have been run to provide sufficient feedback for the AI to improve.

 Silence Therapeutics: Ready for Take-off

I usually do not attend biotech companies’ Investors Days, but since London is not too far away from home, I took advantage of the proximity to get a feel for how the company has matured. 

Silence Therapeutics has long been a player in the area of RNAi trigger design and IP (see also their claim on Alnylam products), but has struggled to come up with compelling therapeutic programs.  It was as if they never really tried.  This can probably be attributed to them having lacked the personnel with the experience of taking an idea through the clinic and onto the market.

It now seems as if they not only got the technology (à focus on GalNAc-RNAi) to the point of clinical maturity, but also have assembled the management with the skill and will to succeed in developing game-changing RNAi drugs.  First up will be SLN124 targeting TMPRSS6 for iron overload disorders with a projected CTA/IND filing in Q4 2018.