Say 'No' to Rosetta Genomics Take-Under by Genoptix

The first wave of efforts to commercialize microRNAs, the close molecular cousin to RNAi, either for diagnostic or therapeutic purposes is about to fizzle out.  With Regulus Therapeutics getting a last chance to prove its worth with clinical data on its Alport's microRNA therapeutic program pending, today's post symbolizes the end of commercial efforts to establish microRNAs as a broadly applied diagnostic platform.  

Rosetta Genomics Surrenders Despite Promising Products

Last month, the Board of Rosetta Genomics, the main torch-bearer of microRNA diagnostics for close to two decades, announced that it was recommending a take-under by Genoptix.  Genoptix is a larger molecular diagnostics player for which Novartis had paid $470M in 2011 and then was acquired by Ampersand last year.  Under the proposed terms as detailed in this proxy statement, the Board has been recommending shareholders to accept what constituted at the time of the announcement a new all-time low price of between $0.6-0.7 per share, that is  ~1/2000, 1/100, or 1/10 of its value 10, 5, and 1 year ago, respectively. 

Please somebody call the Guiness Books of Records.  

Unsurprisingly, instead of admitting their commercial and financial ineptitude, this surrender is blamed on a financial market that would provide no more support microcap molecular diagnostic companies.

Well, if the company had executed properly, it wouldn’t be a microcap company, would it?  And last time I checked, complex molecular black-box diagnostics was the way the industry was going, although I admit that the Wild West culture of this industry with hardly any market entry barriers has been harmful to the industry and burned many an investor. 

There have been at least two products by Rosetta that I thought had real commercial potential.  The first one was a test to determine the tissue origin of a cancer to better inform treatment (RosettaGX Cancer Origin).  Given the trend towards drug regimen that are increasingly aimed at the molecular changes that have occurred during oncogenesis regardless of tissue origin and immuno-oncology approaches that couldn't care any less, the medical relevance of this test might be waning.  This can happen, but doesn’t subtract from the value of quantifying microRNAs for diagnostic purposes per se.

The other test, RosettaGX Reveal, got me (and apparently Genoptix) excited enough to invest in Rosetta, in my case amounting to a ~3% stake of the company (which curiously I had no problem acquiring in a heart-beat since my bids were hit with volume).  

RosettaGX Reveal is intended to prevent the many unnecessary, and medically harmful thyroid gland surgeries performed today on nodules of uncertain cancer potential based on cytology.  The test appears to be conservatively at least as good as the currently leading test by Veracyte in this ~$350M molecular test market (of which 2/3 remain to be tapped) in terms of making a solid recommendation against performing a surgery without missing the malignant ones.  Importantly, Reveal has the advantage of not requiring fresh tissue and can thus be performed on the same cytology sample that the original indeterminate diagnosis had been made.  This is due to the remarkable stability of microRNAs, in contrast to the longer and thus more fragile mRNAs.

The test has shown solid growth since start of commercialization in early 2016, now running at roughly $1M in quarterly sales with lots more room to grow by increasing reimbursement rates (yes, the test is frequently performed without the company getting paid), tapping the 2/3 untapped market, and converting users of competing tests.

Unacceptable Terms to Holders of Ordinary Shares

The reason why I will not vote my 3% of shares in favor of the merger at the upcoming Meeting of Shareholders (note: the 3% should weigh heavier since related parties in the transaction are apparently barred from voting) is that the proposed $0.6-0.7 per share is at a 25% discount from when merger discussions began, at a time when shares were already tumbling daily to new all-time lows.

While letting shareholders feel the pain, convertible debt holders get $2.5M of the $10M pie, obviously worthless warrants get attributed $1.2M, the two key executives get a combined $0.5M good-bye present (in addition to the windfall from the warrants that they will likely be beneficiaries thereof and insurance benefits), and to add insult to injury the transaction cost of the take-under is estimated at $3.3M, about as much as ordinary shareholders would get!

So unless Genoptix sweetens its offer to at least $13.3M, meaning a decent premium and doubling of the consideration to shareholders, I would rather go down with this ship and let this Lipdub clip by Rosetta on Youtube be their lasting memory:

Tekmira Merges to Create HBV Powerhouse as ex-Pharmasset Geniuses Seek an Encore

Last night, Tekmira startled the RNA Therapeutics world by announcing that they would combine with OnCore Biopharma in a merger-of-equals to create the HBV drug development powerhouse.  With eight investigational HBV assets in the pipeline, this model follows the HCV space where combination therapies and companies with a single-minded focus on HCV were able to create tremendous shareholder and patient value.

Most often cited here is Pharmasset which gave Gilead HCV wonderdrug Sovaldi for an at the time (2011) unprecedented $11B.  Of note, OnCore Biopharma was founded by ex-Pharmasset people, including the inventor of Sovaldi.

This also makes it clear that despite paying lip service to the combined Tekmira to continue to value their other liposomal RNA Therapeutics assets ex TKM-HBV1/2, it is a good guess that the RNA Therapeutics platform will not have a long life in the merged company.  This is also because with $100M in cash, the company will have to look for ways to raise capital, some of it in a non-dilutive manner.

Combination and speed

Before the merger, OnCore had already started sweeping up a number of HBV-related assets intended to tackle chronic HBV infections at multiple stages: 1) replication and gene expression; 2) promoting, by stimulating and de-repressing, an immune response against the virus; and 3) even removing cccDNA, thus aiming not only at an already extremely valuable ‘functional cure’, but complete cure.

It is likely that only a multi-pronged approach will be able to achieve that.  The two RNAi candidates by Tekmira which have just entered the clinic are expected to form the cornerstone of that since they target ALL the viral genes.  Moreover, in the challenging chimeric mouse model, TKM-HBV1/2 had an unexpected impact on cccDNA abundance. 

The fact that TKM-HBV is administered intravenously is acceptable for this disease as long as a (functional) cure is achieved after a finite treatment period which, of course, is the goal. By contrast, the other assets contributed by OnCore are largely, if not all oral, including agents designed to inhibit immunosuppressant HBsAg secretion. 

Unlike TKM-HBV, these are at the pre-clinical stage, at least regarding their use for chronic HBV (the TLR9 agonist has already been tested in humans for non-HBV applications).  It is expected that many of them will enter the clinic this or next year. 

Regarding clinical development, the initial goal is to establish the safety of these agents individually before combining members from the three different classes pairwise and in triplicate in phase II.

The fact that all modalities are now under one roof will also greatly accelerate development timelines as, again in analogy to the HCV experience, it would otherwise have made necessary protracted partnering negotiations, sometimes with direct competitors.

Merger a good deal for Tekmira shareholders

Although I bemoan the loss of Tekmira as an RNA Therapeutics platform company, creating the strongest drug developer in the hot HBV space is the more attractive alternative also given the importance of TKM-HBV to Tekmira even before the merger. 

Accordingly, it is more likely that this setup will yield Pharmasset-type returns (say 10x in 3 years), e.g. following an acquisition after showing >40% cure rates in phase IIb, compared to a more balanced RNA Therapeutics platform play which has faced considerable competition from increasingly potent and more convenient technologies. 

Congrats to Tekmira management and Directors. The seeming investor relations breakdown recently has now been explained. Well played!

mdRNA-Cequent, and the RNAi Therapeutics Consolidation Wave Keeps On Rolling

Only 3 months after the Silence-Intradigm merger, synthetic siRNA Therapeutics company mdRNA just announced that they would combine their RNAi Therapeutics assets with that of trans-kingdom RNAi company Cequent Pharmaceuticals. Unlike the Silence-Intradigm merger, however, this merger is less about synergy, more about complementing each others’ strengths, and by this make it successfully through a biotech climate that is only now starting to thaw for platform technologies like RNAi Therapeutics.

Technically an acquisition by mdRNA of Cequent, the transaction benefits mdRNA in that the access to Cequent's cash enable it to finance operations until the end of the year, possibly long enough to convince one or two of their early-stage Big Pharma collaborators to pay $10-20M in upfront payments each for a platform license. Equally important, the transaction transforms mdRNA into a clinical-stage company, with one trial start imminent and possibly 3 additional INDs by the middle of next year (an inflammatory bowel disease program by Cequent and two cancer programs by mdRNA) that should be considerably helped by Cequent’s proven expertise in moving innovative drug candidates into the clinic. This profile, with a stretch-goal of being ready to commercial in 2014 CEQ-508, Cequent’s clinical candidate for the prevention and treatment of colon cancer in familial adenomatous polyposis, or FAP, an orphan disease (reviewed here). This more mature profile may allow the combined company to reach new types of investors.

On the other hand, similar to Intradigm, this transaction provides Cequent’s VC investors with what in the current biotech climate can be considered a successful exit by valuing Cequent at $44M at the time of the announcement, although the present value should be somewhat less following huge volume trades earlier this week. This is also the result of the feat of being able to grow a healthy pipeline of drug candidates in just 4 years, one that is based on a rather unorthodox technology that uses bacteria as delivery agents for the RNAi trigger to sites such as the GI tract (the current focus), genitourinary tract, and skin.

The technology diversification provided by tkRNAi gives the New mdRNA a wider choice of development options. It would be good, however, to keep nourishing the molecular biology of tkRNAi as I believe that within a short period of time, through the wonders of bacterial genetics, significant technology improvements could be achieved. With up to 9 employees contributed by Cequent and about 50 by mdRNA, it remains to be seen to which degree this can be realized in the new company.

I believe both sides and their investors are well served by the outcome and it should be a case where the whole is greater than the sum of its parts. About 60 employees is also about the critical size to be attractive as a partner for Big Pharma with sufficient depth in the various disciplines (RNAi trigger, delivery, regulatory etc), but not too big for it to become too big a cash-burn burden. But this is no time for mdRNA to celebrate for too long. We’ll have to see what Michael French and the new team have up their sleeves next. Meanwhile, there is more potential for consolidation in RNA(i) Therapeutics and mdRNA-Cequent should not be the end of the story during this phase of the global and industry-specific economic cycle.

Disclosure: I have been an advisor for Cequent Pharmaceutical and will only discuss publicly available information. My views on mdRNA’s technologies and tkRNAi can be found by searching this blog with keywords like ‘mdRNA’; ‘Nastech’; ‘Cequent’; and ‘tkRNAi’.

Silence Therapeutics and Intradigm Merge to Offer Complete RNAi Therapeutics Package

Finally, the long wait has come to an end. The just announced imminent merger of publicly traded Silence Therapeutics (UK/Germany) with privately held Intradigm (USA) illustrates that consolidation has also arrived in RNA(i) Therapeutics. The stated objective is for the financially strapped firms to achieve a size sufficient to be considered a one-stop partner for a Big Pharma/Biotech (BP/P from now on) interested in RNAi Therapeutics, and also partly in a bid to enlarge their investor base. This approach is in part inspired by the successes of Alnylam and Sirna Therapeutics which had and have been very successful in monetizing their broad approach towards RNAi Therapeutics. While there are factors speaking for such an approach, times have somewhat changed in RNAi Therapeutics such that the established players such as the Roches and Novartis' are more likely to take a pick-and-choose approach in their partnering strategies. As such, companies that are focused on fewer technologies, especially in delivery, but then can get it right, may be preferred partners for these BP/Bs.

On the other hand, for a BP/B that views a platform partnership as a way to start testing the RNAi Therapeutics waters somewhat more extensively, I am thinking here of the likes of AstraZeneca, Boehringer Ingelheim and Aventis, an enlarged Silence Therapeutics may be worth a second look at least as a cheaper alternative to the gold-standard Alnylam Pharmaceuticals. The risk, however, that I see is that ‘broad’ could easily equal ‘lack of depth’.

As much as the desire to grow in size, the merger was driven by the desperate need of both companies. It is therefore highly likely that the merger will be approved as described in the Admission Document, also because of the holidays which makes it unlikely for a third party to make a too-good-to-refuse buy-out offer. Net of debt and after parallel fund raisings from existing Intradigm shareholders (about £5M) and a placing led by Nomura (about £9M), the combined company should soon have ~$20M in liquid assets, which will give the company about a year’s time to find a platform partner that is willing to part with some decent upfront cash. Especially with part of their operations now based in the US, it may also make sense to pursue a listing on the US markets for their future cash needs.

While the claim is to be a broadly positioned RNAi Therapeutics company, the combined company clearly has a strong bias towards cancer. Therefore, an alternative headline of this blog post would have been ‘Silence Therapeutics and Intradigm to Form Cancer RNAi Therapeutics Powerhouse’. It is here that I suspect most of the scientific synergies and value drivers of this merger will come from. I do not have to describe here the high unmet medical needs in cancer, and it is the unique promise of RNAi Therapeutics to go after the many thus far undruggable, yet well-validated cancer-related targets that makes it an area of such high value proposition to the industry. Since nanoparticles can be targeted to cancers, delivery should be possible: e.g. via the tumor vasculature, the Achilles heel of solid cancers, and antibodies to haematological malignancies. In this regard, Silence Therapeutics and Intradigm bring to the table cationic lipoplexes as a means to knock down genes in the tumor vasculature directly (Silence Therapeutics), also as supported by the literature, and a less validated cationic peptide polymer-based delivery technology by Intradigm ('PolyTran').

But will the proposed merger address the one area next to viable delivery that has been nagging both companies in the past...intellectual property? Clearly, combining two comparably weak patent estates do not a strong one make. A quick glance over what is issued and pending, however, suggests that the patent estates could synergize to a certain degree.

Silence (as most others) has been mostly troubled by the Tuschl and Kreutzer-Limmer patents that make it very difficult for them to find dsRNA lengths to exploit their issued Atu-siRNA design pattern without having to to get a license from Alnylam: blunt-ended dsRNAs with alternate 2’-O-methyl modified RNAs. Atu-027 for example, the combined company’s lead candidate for solid cancers that has entered phase I studies this summer, is a 23bp dsRNA and Tuschl I should be a formidable challenge here. Intradigm, like RXi/Invitrogen’s non-Dicer dsRNAs before (rxRNA solo/Stealth), chose to minimize Tuschl-KL problems by opting for a 25bp blunt-end design, and Silence’s alternating 2’-O-methylation pattern IP might give those a proprietary touch. As I cannot find any evidence that Intradigm currently has any access to 25bp structure-specific patents aside from Fire-Mello, I wonder how extensive the siRNA design IP access to the Zamore (University of Massachusetts) patent estate really is. Zamore’s seminal discoveries centered around the thermodynamic properties of effective siRNA, and if added to the 25bp dsRNAs could further endow those with a proprietary look. One issued patent relates to the stability of the guide RNA 3’ end with the target mRNA and which has implications for RNAi catalytic turnover. This one, however, would serve more the purpose of a design-around fig-leaf, and not necessarily represent a means to exclude others. The more important discovery by Zamore, however, is related to differential end stabilities of siRNA duplexes themselves, a basic siRNA rule that essentially everybody in the field follows. If Intradigm had indeed access to such IP, it could give them some leverage over other companies [maybe somebody reading this can provide me/the blog with more information on the extent of the Intradigm-Zamore relationship].

An area where there should be synergies is a broader gene target base in oncology. I had been wary of Silence’s focus on the PI3K pathway which, despite the well-known importance of this pathway in cancer biology, appears to be too closely connected to the history of the R&D staff for comfort and may have caused them to oversee more promising targets. On the other hand, Intradigm has been pursuing a large list of 50 largely cancer-related gene targets, and has obtained a sequence-specific patent on one of those which should give the enlarged work-force plenty to work on. Despite all these genes, after burning through almost $40M and noise around their initial VEGF-directed lead candidate subsided, Intradigm alone would appear to be some a long time from the clinic. With Silence Therapeutics’ Atu-027 and lipoplexes, the new company can boast at least boast one candidate undergoing clinical evaluation and possibly more to come.

In summary, given the bleak alternatives, the merger makes sense. For the field of RNAi Therapeutics, it may also be good to have companies with sufficient size to attract the attention of investors. Long gone are the days that the Alnylam-Sirna rivalry kept attention levels high. There is, however, a lot to be sorted out for the new company before it can gain the hoped-for traction.

Merging Antisense with RNAi Therapeutics to Create Fitter Companies

Yesterday’s long awaited data presentation on phase III results from ISIS Pharmaceutical’s lead antisense gene knockdown program was met by disappointment in the investor community: ISIS down over 15% on the day. While the exciting news is that the drug, mipomersen, looks like it is very close for approval for the severe, but very rare condition of homozygous familial hypercholesterolemia (hoFH) and importantly also possibly other forms of highly elevated LDL-cholesterol, part of the disappointment may be related to the long-term outlook on antisense for gene/mRNA knockdown: a 27% reduction in ApoB levels following 6 months of 200mg weekly injections with a safety profile (a number of cases of elevated liver enzymes, injection side reactions) that may be adequate for the severe cases of hypercholesterolemia, but not necessarily for less severe diseases. And this is for an organ, the liver, which has one of the best pharmacologies for antisense. Also, while a 27% knockdown may be therapeutic for a few targets, especially in metabolic disease, for most other targets it is insufficient.

Lack of high-quality gene knockdown opportunities would lead to an inefficient use of its capital that includes an enviable $600M+ cash pile and an equally remarkable cash-flow from their ‘satellite businesses’. Maybe partly because of this realization, but also of course because it believes that its IP is transferable to all areas it considers antisense, ISIS is not standing still and continues to innovate in areas such as RNAi Therapeutics and the promising gain-of-function antisense technologies of splice modulation and microRNA inhibition.

On the other side of the fence, RNAi Therapeutics is also facing a challenging investment environment. Capital is particularly difficult to raise for early-stage platform technologies. While some companies such as Alnylam, Tekmira, Sirna Therapeutics (historical example), and mdRNA are making good strides in establishing broad RNAi drug development platforms, this alone does not make up for lack of steady newsflow from mid- to late-stage clinical results that can support rich valuations in biotech. This is also not helped by some obvious mis-steps within the industry itself with the main sins being spending money on lawsuits and prematurely entering programs into the clinic, ironically not least in an attempt to keep investor interest levels high.

By merging with antisense, both the pipeline maturity profile could be enhanced and resources spent more efficiently by avoiding the temptation of entering programs into the clinic prematurely and otherwise weeding out programs that serve to artificially fill pipelines. The latter point, of course, would also apply to the antisense company, and the antisense company would further benefit from gaining access to the most potent and therapeutically promising gene knockdown technology known, RNAi Therapeutics. As the intricate relationship between Alnylam and ISIS Pharmaceuticals or the acquisition of Coley as a launch pad for Pfizer’s RNAi Therapeutics ambitions demonstrate, the scientific barriers for such mergers should be relatively minor. One risk, however, that cannot be ignored, particularly for those companies that have been built for sale, is that by combining various drug development platforms, the new entity may become a less attractive candidate for a Big Pharma acquisition. When it comes to mere survival, however, a combination should be the lesser evil.

I will now briefly discuss three fantasy combinations, at least one of which I would speculate to see within the next year.

1) Alnylam Pharmaceuticals and ISIS Pharmaceuticals (probably not within the next year). Without a doubt the most influential and potent leaders in RNAi Therapeutics and antisense, respectively. Already highly entangled through their IP cross-licensing agreements and microRNA therapeutics spin-off Regulus, a combination would create an almost cash flow-positive dream team with over $1B in cash, blocking IP, unmatched expertise in nucleic acid chemistry, clinical pharmacology, and RNAi Therapeutics. First revenues from the sales of mipomersen and continued IP licensing revenues would support a solid pipeline consisting of mipomersen label extensions, RNAi Therapeutics opportunities for liver and solid cancers, full ownership of the miR-122 program for the treatment of HCV, and transitioning antisense towards splice modulation, microRNA inhibition (with Regulus), and possibly other gain-of-function antisense applications. As part of the re-organization, some programs could easily be sacrificed without punishment by the markets. John Maraganore would be the CEO of the combined company, allowing Stanley Crooke to follow his passion in the science of oligonucleotide therapeutics.

2) mdRNA and AVI Biopharma (how soon?). The transition of antisense for gene knockdown to gain-of-function applications is most noticeable in the case of AVI Biopharma. After many years of attempting gene knockdown with their steric-block morpholinos, the company finds success in applying its technology for the modulation of gene splicing. It is considered the closest competitor to Prosensa’s Duchenne Muscular Dystrophy exon skipping program which has only recently entered an attractive $25M upfront plus multimillion bio$$$ milestone and royalty deal with GSK after a series of high-profile publications on DMD-related exon skipping. The partnership potential of AVI’s DMD program then as well as its recent capital raising should provide the needed capital cushion for the combined company to invest in RNAi Therapeutics for gene knockdown and some new splice modulation opportunities. mdRNA, of course, is scheduled to run out of cash early next year and it would be a miracle if the two companies had not contemplated such a merger, particularly after AVI Biopharma moved in as mdRNA’s neighbor not too long along up from Oregon. With AVI’s cash reserve, the combined company may then find it easier to attract platform partners for mdRNA’s technology further bolstering the financials.

3) Silence Therapeutics and Archemix (not really an antisense company, but close enough). It is almost two months now that Silence announced to be in reverse merger talks. Since then, however, not a word except for so-so news on the results of opposition proceedings at the EPO related to their core patent. What Silence needs is cash (who doesn’t?), and what it can offer is a phase I cancer program, RNAi Therapeutics drug development expertise, and an siRNA structure that is not without use, although facing very serious patent challenges. What Archemix needs with its growing pipeline is access to public markets as evidenced by a previously failed reverse takeover attempt with cash-rich NitroMed, as does by the way Quark Pharmaceuticals which should also be counted as a possible Silence Therapeutics merger candidate. The fact that Silence Therapeutics has some aptamer in its blood line and the increased investment by Archemix into aptamer-mediated delivery of RNAi (Dicerna) and microRNA (miRagen) Therapeutics should help a combined company find a common language. Until any such deal is announced, however, Archemix would have to be prepared though that yet another potential partner will walk away from it last minute as Silence Therapeutics should also be receptive to other offers.

Which one is the most likely combination? Add your vote on the right.