Tuesday, August 2, 2011

Alnylam Says Adverse Event in Tekmira ApoB Trial Was ‘Life-Threatening’

One apparent tactic employed by Alnylam in the ongoing litigation with Tekmira is not to win on arguments, but by coming out with 'revelations' aimed at unsettling Tekmira investors and potential collaborators. A weakened share price and financial position would supposedly make Tekmira more amenable to a light settlement or lowball takeover offer. Much of this has been discussed on this blog before, but today I would like to bring to the attention of the readers here one particularly grave and damaging remark that Alnylam made in their Response to the Amended Complaint, namely that the one case of immunostimulation in the phase I ApoB study that caused Tekmira to stop the trial was ‘life-threatening’:

From the Response:

Further, Alnylam invited Tekmira to join a joint development committee that Alnylam had formed with one of its pharmaceutical partners with the goal of assisting Tekmira and the whole field in advancing LNP technology. Moreover, it is through clinical trials conducted, mainly by Alnylam, that critical elements of Tekmira’s siRNA delivery technology have been validated in the clinic, and Alnylam has provided critical advice and counsel to Tekmira related to their pre-clinical and clinical development activities for their own products. For example, Alnylam’s chief medical officer provided critical and urgent counsel to clinicians attending to a patient in a Tekmira clinical trial that experienced a serious, life-threatening adverse reaction to Tekmira’s drug [emphasis mine].'

Not only does Alnylam make it sound like they are holding little Tekmira’s hands, have the new Chief Medical Officer rush to inept Tekmira's help, and more or less run the trials for them, this statement essentially accuses Tekmira of lying to investors and in front of regulators about the adverse event. These are very serious allegations, some of which by the way were part of the rumor mill even before Alnylam made these statements now in public (!).

These characterizations are in sharp contrast to the way Tekmira used to describe them: serious enough to be taken into consideration for future SNALP development, but not a show-stopper and certainly not life-threatening. Here is how:

Disclosure of adverse event in the phase I ApoB press release:

The primary endpoints of the ApoB SNALP Phase 1 clinical trial were measures of safety and tolerability. ApoB SNALP was well tolerated overall in this study with no evidence of liver toxicity, which was the anticipated dose-limiting toxicity observed in preclinical studies. Of the two subjects treated at the highest dose level, one subject experienced flu-like symptoms consistent with stimulation of the immune system caused by the ApoB siRNA payload. The other subject treated at the highest dose level experienced no side effects. Based on the potential for the immune stimulation to interfere with further dose escalation, Tekmira decided to conclude the trial [emphasis mine].’

If the adverse event had been ‘life-threatening’, then not disclosing this in the press release and subsequent investor discussions would obviously have been misleading.

The clinical details of the adverse event were then disclosed at the Drug Information Association '3rd Oligonucleotide-based Therapeutics Conference' held in Bethesda on March 23, 2010. An important function of these DIA meetings is to further the dialogue between industry and the US regulatory authorities and I assume that the FDA was in attendance and that Tekmira assumed the same when it reported the following:

‘Adverse Event in Suject 190:

- 53 Year old 103 kg male w/ hyperlipidemia

- Second in cohort to be treated with 0.6 mg/kg

- Tolerated infusion well

- ~2.5 hours felt ‘wobbly in legs’

- ~4 hours rigors, vomiting, fever, hypotension, hypoxia, HR 110 BPM

- Treated with Ibuprofin, O2, saline infusion

- Fever resolved in 3 hours

- ~5 hours BP reached nadir

- Patient continued to receive fluids

- IV methylprednisolone (120mg)

- BP, HR, O2 Sat improved

- Patient normal that night

- Returned to study unit the next morning

- Discharged the next day as per protocol

- Patient maintained perfect cogntion throughout episode

Event described as moderate in severity and related to study drug [emphasis mine].'

The account above is consistent with characterizing the event as ‘moderate’ and in no way suggests a ‘life-threatening’ event. While not exactly encouraging, such safety findings are common in clinical trials.

I’m confident that if this comes to trial, this damaging characterization of the ApoB trial will add another few millions to the damages awarded to Tekmira. I simply cannot believe that Tekmira’s management would risk getting in trouble with the SEC and FDA in such a way. There simply is no middle-ground. I know Tekmira shareholders are getting tired of hearing this, an attitude attesting to the success of Alnylam's tactics.

In related News: Alnylam guides down cash as ALN-VSP02 wraps up

Alnylam reported Q2 financial results after the close yesterday. Months after the departure of the former CFO and following the $150M shelf filing, the replacement had the pleasure of announcing that Alnylam is guiding down cash from ‘greater than $275M’ guided 3 and 6 months ago to now ‘greater than $250M’. No explanations were provided for the implied 50% increase in net burn. I hope that the new CFO has retained his ‘sense of humor’- apparently a job requirement at Alnylam [correction 5 August, 2011: in the conference call that followed the press release of the financial results the increase in expenditures were attributed largely to the 5x15TM efforts; not very illuminating really, but there was an explanation].

On the day of the financial results, Alnylam also disclosed that it has completed the phase I study in liver cancer with ALN-VSP02. There was no real new development in this study from the comprehensive data presented at this year’s ASCO (related blog here). What I noticed though is that this drug candidate has now been fully renamed ALN-VSP, dropping the '02' which may have been a painful reminder that Alnylam got all its clinically-relevant LNP delivery from Tekmira [hint: my strong impression based on the VSP conflicts that emerged 4 years ago with the remarks by David Bumcrot is that ‘01’ was a lipidoid formulation, and the ‘02’ formulation resulted from Alnylam giving up and seeking help from Protiva (now part of Tekmira, of course)].


Anonymous said...

Have you been wearing an old felt hat?

I used to enjoy read your blog and gaining some insight on the world of RNAi. Lately, however, you have lost your impartialness and obviously, your mind.

Anonymous said...

So Hausse why would you think the $150 million Alnylam is raising for Tekmira settelment.One would think having snapped up the nucleonics IP for Hep B, they would try and take out their biggest IP compettitor Benitec, considering CSIRO have success over The fire Patent. Isnt Alnylam who is behind the UK patent challange.

Anonymous said...

Well. There are definitely camps and believers for each side with the lawsuit. Honestly, is the current delivery system working out in the clinic? Is there something each side not disclosing to the public? Although Merck indicated "not pulling out", but they certainly are pulling back. Granted, a lot of studies are needed for IND, but after Tekmira stopped their trial they are really slow in getting back on the clinical trial track. The worst scenario for the RNAi field is to have lost FDA's confidence.

Anonymous said...

Akshay Vaishnaw, according to Alnylam's own press releases, was SVP, Clinical Research from Jan 2009 through June, 2011. His promotion to Chief Medical offer was announced in In a June 13, 2011 company press release.

As you note, Dirk, the AEs that prompted the subsequent "counsel" by "their Chief Medical Officer" on page 35 of the Alnylam Response to the Amended Complaint by Tekmira (dated June 28, 2011) were first disclosed in 2010.

So did Vaishhnaw, in his capacity as Chief Medical Officer, give his counsel regarding the aforementioned AEs to Tekmira a year or more subsequent to their initial presentation?
Or, did Vaishnaw provide his clinical counsel immediately subsequent to his learning of the AEs?
If the former is the case, then provision of the counsel was no great reflection on the clinical acumen of Dr. Vaishnaw.

However, if the latter is true, then inclusion of Vaishaw's title of Chief Medical Officer is entirely irrelevant (Imagine it being reported that "President Obama" was found to have made a bad call while refereeing a pick up basketball game in Hawaii in 1977).

Whether Tekmira's allegations are true or not I can't determine. However, the facts above can be construed to indicate that Alnylam is seeking (in part or in whole?) to counter Tekmira's claims by innuendo and carefully constructed deception.

Anonymous said...

Dirk, I've read your blog with regularity for three years. My view is you (generally) have presented critical and substantiated analyses of the activities of companies working in the RNAi space. However, your posts over the last several months betray a recurrent and barely veiled bias in favor of Tekmira and against Alnylam.

It would appear to me that if on the one hand, you provide fee-based consulting re: RNAi therapeutics and on the other hand, you concurrently author blog posts in said area with such an overt bias, you risk your professional credibility in this area. You of course provide an explicit disclaimer that this blog is for "entertainment", purposes but, I have no doubt it also serves as a major advertising vehicle for your consulting services. Any response to my comments?

That being said, I am no shill for Alnylam. Your most recent post details what many would consider to be a base and calculated attempt by Alnylam executive management to weaken Tekmira's legal position against them by means other than documentary evidence.

John and Akshay, shame on the both of you.

Dirk Haussecker said...

Appreciate your comment. If you think I'm trying to hide my 'bias'- I'm not. I've followed the Alnylam-Tekmira relationship very closely over the years and concluded that Alnylam forcefully tried to put Tekmira in an impossible position and destroy them as a result.

I don't think Alnylam would have cried a tear if that happened.

In fact, I had been worried about what was going on months before Tekmira filed its lawsuit and even had a phone call with John Maraganore complaining to him that I strongly disagreed with how they treated Tekmira (AlCana, press releases and all). At that point, I did not even know about the damaging disclosure of Tekmira trade secrets and proprietary information to Novartis and Takeda.

It's a shame. Alnylam's mgmt is highly skilled in many regards and I have learned a lot by following them build Alnylam. They do, however, lack empathy.

I don't know how you want me to comment on this issue to which the fates of most major efforts in the industry have been and still are tied: 'Yes, Alnylam may well have plotted the demise of Tekmira, but hey this is a little price to pay since as a result we now have one financially strong industry player that might make it over to the other side of the profit gap.'?

I believe that Tekmira and their shareholders, of which I am one, would disagree and feel like Alnylam has taken from them.

If my arguments don't convince you or companies interested in my services, then that might also be my loss, I agree.

Anonymous said...

Dirk, thanks for your response to my query. I confess my intent was to provoke a more detailed explanation of the origins your particular disposition towards Alnylam.

I'm completely aligned with your assessment of Alnylam's a response to Tekmira's Amended Complaint. Its loathsome and unbecoming of the self-professed "leader" in the field of RNAi Therapeutics. One is left with the near inescapable conclusion that the manner in which they recapitulated and reframed the AEs associated with the ApoB clinical trial is an act of desperation. As the forth post in this string details, Dr. Akshay Vaishnaw did not hold the title of CMO when the AEs presented. What reprehensible bullshit.

Alnylam employees should carefully read their company's Response to Tekmira's Amended Complaint. They then should demand that John Maragnore, Barry Greene, Akshay Vaishnaw and the participating legal team explain and substantiate the wording of the relevant text.

By Dirk Haussecker. All rights reserved.

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