Arrowhead Research, Focus on RNAi Therapeutics

Arrowhead Research just announced the publication of a scientific paper detailing its fundamentally new DPC delivery approach (discussed here before).  Except for noting that this study is a proof-of-concept one only and, based on recent conference presentations, clinically more relevant formulations have been developed, I am feeling more compelled to talk about my thoughts on Arrowhead’s corporate strategy than to give you are run-down of the paper that you can also read yourself here.

A Dubious Past

When I used to think of Arrowhead, a company came to mind that was constantly chasing the latest hot area in science and technology to raise the next round of money, and never pursuing anything in great detail.  And it is great detail that is required if you really want to make a product, especially a drug.  It got worse during the economic downturn when the company claimed to be a broad RNAi platform play and did not even have a lab to show.  As Benitec is demonstrating, not having a lab while acting like a platform play means that you are wasting time while dwindling away cash resources.

The Roche Acquisition- A New Beginning?

Then suddenly, Arrowhead unexpectedly emerged with the Roche RNAi asset scalp in hand.  Overnight, the little company acquired assets from Roche on which the Big Pharma had spent ~$700M. including a vibrant research organization in Madison, Wisconsin.  Although this finally got the company that missing lab, it also seemed a huge financial gamble at a time when RNAi Therapeutics sentiment was at its bleakest (late 2011, a month before the ALN-TTR01 presentation).  How would such a small cap biotech company fund the enlarged operation?  Yes, you can buy castles in France for a token Euro, but can you actually afford to live in them?

That bet likely depended on the outcome of two issues: 1) RNAi Therapeutics sentiment had to turn around in time so as to provide upward pressure to the valuations of RNAi Therapeutics companies.  This would help Arrowhead Research raise the needed capital in a shareholder-friendly manner; 2) The DPC delivery platform needed to show signs that it was finally moving into the clinic.

The first bet worked out as we know.  RNAi Therapeutics sentiment improved dramatically over the last 12 months, albeit from a very low base.  Unfortunately, Arrowhead Research happens to be the worst performing publicly traded RNAi Therapeutics company over that period.  The second bet actually also worked out as the recently reported data on decent knockdown efficacy in non-human primates at acceptable safety strongly suggest.  Moreover, the latest advances in DPC subcutaneous delivery provide the technology with added value based on technical differentiation.  Without having maintained the research operation, we would not have seen such progress.      

When Arrowhead made the acquisition, I thought it was too bold and that it would destroy most shareholder value due to dilution.  Although the stock has kept decreasing and new shares were issued, it probably has not fully destroyed it (yet)- so I have to give at least some credit to Arrowhead’s management.

What the H…? Arrowhead Buys a Peptide Library

Turns out though that the boundary between what is a visionary or a delusional company can be a blurry one.  There is reason to believe for this to be the case here after Arrowhead decided to buy the peptide targeting library from Alvos.  As peptide drug conjugates and DPCs are both targeted technologies, the company is pursuing a strategy as a Grand Targeted Therapeutics company dominating all areas of targeted therapeutics.  It also claims that the peptides and DPCs can be used synergistically.  For various reasons, forcing the Alvos peptides on the DPCs does not make sense for the company- trust me.

I agree that targeted therapeutics is the future of the industry and it is a nice vision for an ambitious company with a strong cash flow and $3B on the balance sheet.  But even if this were the case, I doubt that a realistic Board of Directors would approve such a strategy.  The reality is that getting DPC delivery to work alone is more than enough on Arrowhead's plate.  Licensing out the peptide library would just be peanuts and consume much of the energy required for more worthwhile business development efforts.

Worse, the acquisition of the peptide library makes Arrowhead look like the old technology fashion-chasing company.  This impression is further strengthened by the emphasis of the peptide library over RNAi Therapeutics in the latest investor presentations. Biotech investors have learned to avoid such increasingly rare traps. 

Would you invest in Arrowhead Research?  Take part in the survey in the top right-hand corner.

Tuschl Patents Stage Remarkable Comeback in US

[please note the changes below after I discovered that I missed the last claim amendments, as correctly pointed out by a commenter]

Alnylam announced today that the US patent office had issued 3 Notices of Allowance in recent weeks pertaining to the Tuschl patent estate.  Before your eyes glace over, read on, it's actually one of the few important patent news.  

The granted composition-of-matter claims cover very broadly 19-25bp RNAi triggers, independent of structure.  This is a stark departure from the trend that had materialized in the Tuschl patent applications where Tuschl I seemed to get relegated to treating diseases of fly lysates and Tuschl II suffering from double-patenting issues over Tuschl I.

Claim 1 of allowed patent application 12/537602:

1. Isolated double-stranded RNA molecule, wherein each RNA strand has a length from 19-25 nucleotides, wherein said RNA molecule is capable of target-specific nucleic acid modifications.

1.  An isolated double-stranded RNA molecule, which is a non-enzymatically processed RNA molecule, wherein: (i) each RNA strand independently consists of 19-25 nucleotides in length, and (ii) at least one RNA strand forms a single-stranded 3'-overhang from 1 to 5 nucleotides, wherein said RNA molecule is capable of target-specific RNA interference.

The reason why such a comeback was possible can be traced back to the settlement over the Tuschl patents 'with Merck' in early 2011.  This allowed the Tuschl I and II prosecutions to be aligned such that the double-patenting issue for the 3' overhang claim could be overcome such that the broadness of the Tuschl I RNAi triggers could be rescued into the valuable human therapeutic uses. 

Among those without RNAi trigger licenses from Alnylam, Silence Therapeutics (and its partners, especially Quark) should be hit particularly hard by the latest development: 19bp RNAi triggers are no place to hide any more.   

There are thus two monsters of RNAi trigger patents that consequently co-exist in the commercially very important US market: Baulcombe for almost all types of therapeutically useful double-strand RNA lengths (20-24/30bp; see here) and Tuschl for the desirable 3' overhang feature of RNAi triggers.  It is unclear to me how two patents can essentially claim the same.  Either the patent office is aware of this and is satisfied with ultra-fine semantics distinguishing the two, or this is an issue worth reconsidering.

Another indication that the last word might not have been spoken may be the multiple requests by Alnylam (i.e. their law firm) to expunge certain materials that were rendered during the Tuschl patent prosecutions (possibly relating to timing and nature of the claimed invention), but are deemed trade secrets by Alnylam (can’t help but smile, here). Has Utah taken notes in time?

RNAi and Antisense Targeting the Same Gene: Not a Zero-Sum Game

Transthyretin-mediated amyloidosis has become the single-most important factor for the 3-5 year valuation of certainly Alnylam, and possibly ISIS Pharmaceuticals as well. After TTR, Z-alpha-1-antitrypsin (Z-AAT) is gearing up as the next Alnylam(RNAi)-ISIS(antisense) battleground. Expect to hear competitive language from the two camps why their approach will prove superior over the other.  It is, however, worth keeping in mind that having two candidates race towards approval can also have significant pie-enlarging benefits.

Raising Awareness and Pressuring Regulators

A good competition will attract attention, from patient groups, physicians, regulators, and the investor community.  Patient groups and physicians will be primed that after years of lacking treatment options, the time for change has come.  We have seen this with the trifecta ofweight-loss drug candidates, two of which have recently been virtually willed into approval.  Given the enormous problem of obesity, it became politically untenable to further withhold treatment options.  Eventually, the regulators were forced to give in to the pressure despite their original objections over safety.

Closer to home, similar awareness and pressure is being brought to bear on getting exon-skipping oligonucleotides approved for the treatment of Duchenne Muscular Dystrophy, stoked by the competition between Prosensa/GSK and Sarepta .  If you caution about hurried, aka accelerated approval, then you are readily labeled as a heartless misanthrope.  Similarly, the homozygous familial hypercholesterolemia population has already been educated, targeted, and friended by both patient-access specialist Genzyme and competitor Aegerion and probably strongly expect the new drug approvals.  

Understand that these comments are not meant to be judgments on the respective drug candidates, but just the way I view current dynamics.  In fact, I agree that developing drugs for many of the rare and severe (orphan) diseases requires more risk-taking, usually biomarker-based approaches, and that not too long ago patient needs were not sufficiently considered in a highly risk-averse regulatory climate.

The TTR Amyloidosis Race

Given that Pfizer’s drug candidate tafamidis does not appear about to revolutionize the treatment of TTR amyloidosis, I see similar pressure building for the approvals of gene knockdown approaches ALN-TTR02 and ISIS-TTRRx in 2015-6.  The intense competition between ISIS and Alnylam will provide good fodder for the press (just as it does for this blog), engage the minds and pad the pockets of key opinion leaders and consequently raise the expectations of the public and hopes of those suffering from the disease.

While I have 2015-6 approvals baked into my projections of the RNAi Therapeutics story, I wouldn’t mind a year’s delay if the competitive dynamics would allow for it.  In fact, I expect the FDA to manipulate the process in a way that both drug candidates will come before an AdCom panel together, making the obsession with speed over good science even more so nonsensical.

My problem with ISIS and GSK speeding straight into a phase III study after a single phase I study is that they do not seem to have identified a suitable dosing regimen: 400mg/week good efficacy (-81% knockdown), but probably too high a dose from what we know about the safety of phosphorothioate oligonucleotides; 200mg/week could fare better in terms of safety, but has shown only modest knockdown efficacy (-44% knockdown).  In my opinion, another dose-finding study would be in order under normal circumstances.

[Update 29Nov2012: The Clinicaltrials.gov entry for the upcoming phaseII/III ISIS-TTRRx trial shows that the companies have chosen the stab-in-the-dark 300mg/week dose.  Although the January 2012 phase I results press release made no mention of such a cohort, the June 2012 Annual Shareholder Meeting TTR poster shows data from a 300mg cohort (~70% knockdown).  Unlike all the other cohorts were 90+ day data, the 300mg cohort data was less than 50 days.  It thus looks like a 300mg cohort was included post-hoc. Unfortunately, ISIS has chosen not to list the phase I trial on clinicaltrials.gov.]

This concern over uncertain dosing schedules also applies to Alnylam's ALN-TTR02 (-87% peak knockdown, -67% knockdown after 28 days following single dose) where the current ‘multi-dose’ phase II study only seems to cover two doses.  You would hope that Alnylam presses hard to amend the study to include further doses to gain more experience with the repeat-dosing pharmacology of ALN-TTR02 before betting their house on a single pivotal phase III trial.

Once approvals are obtained, however, the beneficial aspects of competition should disappear quickly especially when small orphan disease populations are involved.  But until then, the race towards approval should free energies allowing TTR amyloidosis to become the first real commercial success story of either RNAi Therapeutics or RNaseH antisense.

Who do you think will win the TTR race? Take part in the survey (upper right hand corner).   

Demystifying ddRNAi Trigger Design

A somewhat vexing problem with DNA-directed RNAi (ddRNAi) has been the heterogeneous mixture of small RNAs generated from a typical expression vector.  Not only will this compromise knockdown efficacy through competition for RISC loading, it also poses a safety risk by increasing the number of off-target genes.  For a long time, heterogeneous ddRNAi trigger processing had been accepted as a way of life- as long as the efficacy was right you would not waste too many thoughts on those multiple bands on your Northern blot.  

Choosing the double-strand length of a ddRNAi trigger has also been more art than science.  Different sizes, usually between 19 and 29bp facilitate potent gene knockdown, but there have been few studies looking at the consequence of size on the uniformity of hairpin processing.   

Next-generation sequencing technology is changing these attitudes.  In a paper that appeared last week in CELL, Gu et al. from the Kay lab in Stanford showed that next-gen sequencing is a powerful tool to detect which small RNA species are generated from a given ddRNAi template plus their relative quantities.  Moreover, through an iterative process of structural change and sequencing, a key structural feature causing the Dicer enzyme make just one predictable cut could be identified.  Without going into much detail, a simple 21 base-pair hairpin yields the purest results.

Commercial ddRNAi trigger landscape getting rusty  

While the clinical validation of SNALP delivery technology has allowed synthetic RNAi trigger-based Tekmira and Alnylam to turn around their fortunes and should also increase general interest in the technology, there seem to be no commercial players left in the ddRNAi Therapeutics arena able to champion and refine the platform. 

Benitec is pre-occupied with trying to monetize IP that is rapidly losing in value due to its age and as a result failing to become a real biotechnology company with a lab.  The two viral delivery companies that once had some ddRNAi ambitions, AMT (AAV) and Oxford Biomedica (lentivirus), either went out of business and/or lack the requisite RNAi molecular biology expertise.  And the other groups developing ddRNAi Therapeutics, including Calimmune and Genables are de facto one-product, disease-focused companies.  This is unfortunate as there should be room for at least one or two ddRNAi Therapeutics platform companies.

Such a company would have expanded on the basic dsRNA concept and would thus have kept its IP estate fresh, eventually forcing others to take a license as simply running out the patent clock would not have been an option.  Such IP would include discoveries like the one made by Gu and colleagues.  On a more positive note, it is possible that the current revival of gene therapy after a decade of neglect and scorn will eventually carry ddRNAi Therapeutics along with it.

Tekmira Regains Control over Leading Delivery Technology

When Tekmira filed its lawsuit against Alnylam in March 2011, it found itself in an impossible position: Alnylam’s apparent mis-use of SNALP-related trade secrets not only diminished their strategic value to Tekmira, including depriving it of potential pharmaceutical partnerships, Tekmira may even not have been able to use the technology it invented.  As a result, it might have been left to die in a little cage with ‘1^st generation’ technology as its technology was making rapid progress.    

Cash and Control

Based on the disclosed terms of last night’s settlement with Alnylam (Tekmira's version here, Alnylam's version here), Tekmira got essentially all that it needed: control over its leading systemic RNAi Therapeutics delivery technology, including the contested MC3 lipids of which the IP was assigned to Tekmira, and a $65-75M payment (~$16-18M of which will go to pay outstanding legal fees).  The payment, of course, will finally allow the otherwise financially conservative company to push forward their development pipeline with interesting therapeutic candidates such as TKM-PLK1.  Notably, as part of the settlement, Tekmira obtained full ownership over this candidate which I believe addresses one of the most exciting RNAi targets in oncology. According to the Q3 financial results, also released today, TKM-PLK1 has been making good progress, including showing signs of drug activity and will advance into phase II studies next year.

Beyond the cash, the new IP licensing arrangement between the companies is at least as valuable.  Importantly, Tekmira has regained exclusive sub-licensing rights to ‘LNP intellectual property’, an incredibly important part of the settlement as before that Alnylam enjoyed such control, mainly via its rights to the Semple-Wheeler IP covering important aspects of ionizable SNALP technology.  This should open the door for Tekmira to enter into the long-expected pharmaceutical partnerships. Novartis and Takeda are here the most obvious near-term candidates for platform-type relationships.

Assuming that the new relationship is not restricted to RNAi Therapeutics, an added bonus is that the settlement could similarly pave the way for relationships in the microRNA Therapeutics space, particularly for the delivery of microRNA mimics.  Only recently, privately-held Mirna Therapeutics made headlines by raising $34.5M to fund the development of a microRNA mimic into the clinic, indicating the significant interest in this area of drug development.

Value of the Trade Secrets

Less clear is the damage to the trade secrets that were at the center of the dispute and on which much of Tekmira’s strategic advantage rested.  Numerous groups and companies have attempted home-brew liposomal RNAi trigger delivery, but only Tekmira’s technology has made it into the clinic.  Especially the ability to formulate and manufacture the particles is what set Tekmira apart from the competition.  In their press release, however, Alnylam stated their intention to use its own LNP manufacturing capabilities.  Apparently, it has already established such GMP manufacturing capability over the last year (in a separate building apparently for added suspense).  Assuming that Tekmira did not assist them in establishing such manufacturing, this indicates that the number of people with critical knowledge to the trade secrets has grown.  This can be particularly a problem in the wake of lay-offs in a place like biotech world capital Cambridge, Mass. 

Still, I assume there to be significant hurdles for other companies to replicate Tekmira’s processes, and with its liposomal experts, Tekmira should continue to lead in advancing SNALP delivery, making it the liposomal delivery partner of choice.

With cash of around $50M (excluding the $10M which are contingent on likely 2013 development milestones for ALN-VSP02 and ALN-TTR02), partnerships likely to come in due to the clarified IP situation, the $141M DoD Ebola biodefense contract (a new more potent and safer formulation will be used) and the income stream from Talon Therapeutics, Tekmira has thus emerged as the vibrant RNAi Therapeutics company it should have become 3 years ago.  Nevertheless, today's terms underline the value of Tekmira and RNAi delivery in general.  Exciting times ahead.

Cautionary Statements in Alnylam's SEC Filing

Today, I would like to post excerpts from Alnylam's most recent quarterly filing with the SEC (10-Q, here), comments that are related to the trade secret litigation between Alnylam and Tekmira.  Since the use of cautionary language is strongly encouraged for public companies to protect themselves from shareholder lawsuits, such filings are a great way to glean some insights into how they think about legal proceedings.

Although Alnylam claims that a loss, including resulting from a settlement, is 'less than probable', they certainly acknowledge the significant potential liability.  For the first time, Alnylam discloses what it considers an appropriate damage estimate- a meager (less than) $4.4M, but which makes me wonder whether the manufacturing accusations have been more or less admitted to (highlights are mine):

        'The Company has not recorded an estimate of the possible loss associated with this legal proceeding. Although the plaintiffs have not specified in their complaint the amount of monetary damages they are seeking, they have served an expert report estimating their damages under a variety of theories, which was subsequently updated. These theories include the purported lost value of the plaintiffs’ trade secrets, calculated using two approaches, as well as the Company’s alleged unjust enrichment resulting from the purported misappropriation of the plaintiffs’ trade secrets, again using multiple approaches. The Company believes that under the applicable law the plaintiffs are not entitled to aggregate multiple theories, but the plaintiffs have argued to the Court that they are entitled to do so. The various theories of plaintiffs’ damages under the plaintiffs’ most recent expert report range from approximately $61 million to $234 million. If the theories of monetary recovery included in the plaintiffs’ most recent expert report were aggregated, it would result in damages within a range of approximately $310 million to $484 million. In addition, under one of the plaintiffs’ claims, any compensatory damage award sum could be subject to doubling or trebling, which could increase the potential damages up to approximately $1.5 billion, and the plaintiffs would also be entitled to recover their reasonable attorneys’ fees. As of June 30, 2012, Tekmira reported a contingent liability to their lead counsel in the amount of $12.5 million, which is likely significantly higher as of the date of this filing. The plaintiffs are also seeking prejudgment interest.

The Company denies any wrongdoing and believes that the plaintiffs’ estimate of their purported compensatory damages is grossly overstated and based on faulty reasoning. The Company has served expert reports supporting the Company’s position that it is not liable on the plaintiffs’ claims, as well as an expert report on damages, which opines that the plaintiffs’ damages estimates are unreliable and, if their expert conducted an appropriate analysis under one of his approaches, damages in the event of an adverse finding on the liability issues would be less than $4.4 million. This amount could be subject to doubling or trebling, and the plaintiffs would also be entitled to recover their reasonable attorneys’ fees and potentially prejudgment interest. However, notwithstanding the Company’s expert report, damages would be much greater if the case is tried to a verdict, and the jury finds the Company liable and also accepts the plaintiffs’ theories of monetary damages discussed above.

As the trial date approaches, the Company is pursuing all reasonable approaches available to it to reach resolution of this matter, including both settlement negotiations and full trial preparation. The Company does not currently believe that a settlement of this legal proceeding is probable, in accordance with ASC 450, Accounting for Contingencies, due to a number of factors; however, the Company intends to continue to evaluate all possibilities for resolution of this matter, including a potential settlement.

Significant judgment is required to determine both the likelihood of a loss and the estimated amount of any such loss. The Company currently believes that the likelihood of a loss is more than remote but less than probable, in accordance with ASC 450, Accounting for Contingencies, and is unable to estimate a reasonable range of loss for this legal proceeding due to many factors.'

It is also of interest that there was a statement on the recent Genzyme deal which strongly indicated that it got done without Tekmira's consent.  Note that Tekmira would stand to receive part of the financials of that deal just as ISIS got a cut, plus Tekmira would have to be involved as regards ALN-TTR02 manufacturing:

'The Company has agreed to indemnify Genzyme for legal costs and other losses or amounts required to be paid by Genzyme, if any, in connection with or related to certain of the Company’s ongoing litigation matters.' 

Finally, Alnylam discusses that it is important to be able to manufacture RNAi Therapeutics candidates themselves, including LNP delivery.  It would not be surprising if building such capabilities had already been a major effort at the company.  Such a move would also support that the two companies rather than merging will go their separate ways after all is said and done:

'Given the limited number of suppliers for our delivery technology and other materials, in the future, we expect to develop our own capabilities to manufacture drug substance, including siRNAs and siRNA conjugates, and/or finished drug product, including LNP formulations, as permitted under our manufacturing agreement with Tekmira, for human clinical use.'

The jury trial is slated to start next week.  Alnylam won't have to face analysts on a conference call for another 3 months, and tonight all the attention will be with the outcome of the US elections.  If there were a settlement, tonight would be the night to announce it.

Bullish on RNAi Therapeutics

Attending the Oligonucleotide Therapeutics Society meeting last week in Boston, I could sense a new bullishness around RNAi Therapeutics like I haven’t in a long time.   

Big Pharma: Tipping the Scales in Favor of RNAi Therapeutics

Over the last year, we have been witness to the clinical successes of Tekmira’s SNALP delivery that literally saved the sector.  After nightmarish years, these results had investors enjoy the doubling and tripling of the share prices of companies like Alnylam, Tekmira, and even non-SNALP players such as Silence Therapeutics.

For the next leg of expanding investments in RNAi Therapeutics, a renewed, publicly visible commitment by Big Pharma would be important.  With Genzyme taking a license to Alnylam’s transthyretin amyloidosis program, a first step in that direction has been just made.  On the platform side, it is worth noting that the two most significant Big Pharma players in RNAi Therapeutics, Merck and Novartis, were also represented at the conference.  One can only hope that the current RNAi Therapeutics clinical and scientific tailwind will give their internal champions the ammunition to push the technology into the clinic in the next 2-3 years and therefore escape the Sword of Damocles that surely must have been felt dangling above them.

Unfortunately, if these two companies, like so many others it seems, big and small, insist on using ‘their’ own delivery technologies, chances for that will be much reduced.  With all due respect, but the presentation on RNAi delivery by Merck was just a review of the most advanced systemic delivery technologies, SNALP (Tekmira), DPCs (Arrowhead Research), and GalNAcs (Alnylam) exemplified by Merck’s homebrew versions.  Somebody needs to show me the math behind it- I just don’t get it.  The only explanation for me is pride and the resistance against collaborating after having invested internally so much.

A re-commitment towards RNAi Therapeutics should also be at the expense of ‘naked’ RNaseH antisense.  Although in his keynote speech, Alnylam’s CEO made a point of congratulating ISIS CEO Stan Crooke (sitting in the first row) on the recent mipomersen Advisory Panel, there was considerable talk during the conference about antisense-related toxicity, also as regards the high-affinity versions.   And even Stan Crooke could not help but admit that the RNAi Therapeutics results have ‘exceeded [his] expectations’.  However, since ISIS claims ownership over RNAi Therapeutics, as it does indeed over most of oligonucleotide therapeutics anyway, his pain should be limited if indeed he believes what he is saying [note: Dr. Crooke in discussing the safety of mipomersen went as far as saying that there has been no imbalance in its safety profile compared to placebo, and when there was an imbalance, it was in favor of mipomersen...for a starkly different view, see here].

A Breath of Fresh Air in Delivery

A conference highlight were the new results from Arrowhead Research on their new DPC delivery, a conjugate approach.  Potent gene knockdowns in the liver with an apparently reassuring safety profile in non-human primates using subcutaneous delivery is certainly deserving of some serious attention.  Having had systemic delivery of synthetic RNAi triggers almost for themselves for the last few years, Tekmira seems to be finally getting some company- although in terms of validation, SNALP is still years ahead and more de-risked.  Such increased diversity of approaches should also be good for attracting general interest to the sector as it would be viewed as more vibrant and with more disease opportunities.

5 Reasons to be Bullish on RNAi Therapeutics

1)      Clinical results show that RNAi Therapeutics in Man can be made to work (Tekmira’s SNALP delivery);

2)      RNAi Therapeutics ideally suited to address orphan disease, the hottest category in drug development;

3)      RNAi Therapeutics has taken the lead over RNaseH antisense for gene knockdown;

4)      Big Pharma coming back to RNAi Therapeutics;

      5)      Vibrancy of sector increasing (e.g. recent results on Arrowhead’s DPC technology). 

A Side Note on the Conference

To some degree reflecting the increasing maturity of Oligonucleotide Therapeutics, the 4-day program did not include important programs in the field.  Not only was Tekmira notably missing, but also efforts such as Dynavax’ important HepB vaccine candidate that could soon allow oligonucleotide ‘therapeutics’ to touch many lives.  Moreover, the industry-academia balance was tilted in favor of industry like I have not seen before.