Some investors get mad whenever I write or tweet something critical of Ionis Pharmaceuticals (IONS - Get Report) , the antisense drug developer.

This week's Biotech Stock Mailbag focuses on Ionis, formerly known as Isis Pharmaceuticals.

Earlier this week, Ionis and partner Biogen (BIIB - Get Report) reported a positive outcome from a study of the experimental drug nusinersen in infants with a rare and truly terrible disease that causes muscles to atrophy.

I wrote an article about the nusinersen news, but when I remarked on Twitter that 1) the results were expected; 2) the drug isn't worth much to Ionis because Biogen owns most of the economic rights; and 3) the nusinersen data don't provide much read-through to the rest of Ionis' pipeline, some of my followers -- Ionis fans -- responded with angry tweets.

@adamfeuerstein @AndyBiotech you can be a real idiot

— Dirk Haussecker (@RNAiAnalyst) August 1, 2016

@adamfeuerstein How many drugs have you created in your lifetime Adam? Btw bathtub crank and shoddy homebrew don't count.

— Tim Moser (@who_can_tell) August 1, 2016

@adamfeuerstein why do you hold a grudge against Stan and IONS?

— GrandPrix65 (@1974Grandprix) August 1, 2016

I don't hold a grudge against Ionis or founder and CEO Stanley Crooke.

Ionis deserves praise for establishing a broad pipeline of antisense drugs. The company has done well to find pharma partners for many of its projects. But the knock on Ionis -- a widely shared criticism on Wall Street and deserved in my opinion -- is an inability to finish the job. Ionis was founded in 1989 but has yet to bring a drug to market that was a commercial success. [Two approved Ionis drugs sold next to nothing.]

And as the incident below illustrates, there are legitimate concerns about what Ionis discloses about the safety and tolerability of its antisense drugs in clinical trials.

In January 2013, days before the biotech industry gathered in San Francisco for the J.P. Morgan Healthcare Conference, Ionis (Isis, then) emailed copies of its newly updated corporate presentation to institutional investors scheduled to meet with the company's executives.

Unbeknownst to Ionis, the presentation formatted for investors included, by mistake, information meant for internal eyes only. Three slides in the deck titled "Lessons Learned From Kynamro" summarized Ionis' experience dealing with the Food and Drug Administration and Wall Street during the contentious clinical review of the cholesterol-lowering drug.

Ionis realized quickly that privileged information had been given to investors by mistake. The company sent out a corrected version of its corporate presentation with the "Lessons Learned From Kynamro" slides removed.

But the old slides could not be taken back and they've circulated among investors.

One of these internal Ionis slides focused on "development tactics" for the company's future antisense drugs.

Here is that slide, which I obtained (along with the entire presentation) from an investor who got it from Ionis:

One troubling interpretation of this slide suggests Ionis, learning from the painful Kyanamro experience, intended to under-report side effects of its other antisense drugs in mid- and late-stage clinical trials. "ISR" is shorthand for injection site reactions; "FLS" is flu-like symptoms.

Ionis is committed to the full disclosure of all side effects of antisense drugs in its pipeline, the company has told me, in response to questions about this slide. The slide above does not represent an effort to under-report safety reporting of its drugs, Ionis says. Instead, the slide explains the company's decision to revert back to standard practice in reporting adverse events from clinical trials, Ionis says, because during the Kynamro clinical trials, extra data on adverse events were collected.

It's important to remember these slides were created two months after Ionis emerged bruised from an October 2012 FDA advisory committee meeting convened to review Kynamro, a drug the company had long touted as a potential blockbuster.

At that meeting, the FDA raised concerns about serious side effects and tolerability issues related to Kynamro injections. More than half of the patients enrolled in the pivotal Kynamro studies dropped out early to due to side effects.

Investors first learned about the extent of Kynamro's safety issues at the FDA meeting because Ionis and partner Genzyme had not fully disclosed results from the drug's clinical trials. This is why Ionis suffers from a perception that it hides bad clinical data.

Kynamro managed to win a positive recommendation from the advisory panel and the FDA later approved the drug, but the disclosure of safety problems caused permanent damage. Kynamro was a commercial flop.

Even with the Ionis denial of any wrongdoing, investors who remember the Kynamro experience and have seen this slide tell me it makes them think twice and be less trusting of clinical data reported by the company, even three years later.

Safety and tolerability issues continue to dog Ionis' antisense drug pipeline despite promised refinements to the technology. Most recently, worrisome cases of serious platelet declines (thrombocytopenia) were reported in patients treated with IONIS-TTR and volanesorsen, two of the company's antisense drugs in phase III studies.

Back to the 2013 presentation. I mentioned the original Ionis investor slide deck accidentally containing the privileged, insider-eyes information was replaced by a cleaned-up version. Compare the slide above to its replacement below:


You see why Ionis has trust issues?

Charlie M. writes, "The nusinersen data proves your improper bias against Ionis and shows me that you don't know what you're talking about when it comes to this company. You keep bashing the stock and they keep delivering fantastic drugs."

Charlie's email came in response to these tweets:

1/ $IONS nusinersen worth ~$1.1B EV assuming 15% royalty on $2B peak sales in 2021. 8x multiple...

— Adam Feuerstein (@adamfeuerstein) August 1, 2016

2/ $IONS Call nusinersen $10/shr + $7/shr cash = $23/shr for rest of (troubled) antisense pipeline? Someone is sniffing glue!

— Adam Feuerstein (@adamfeuerstein) August 1, 2016

Putting aside the "sniffing glue" snark, nusinersen is a bigger drug for Biogen than for Ionis. That's what happens when you sign away most of the drug's commercial rights to a partner.

You can plug in your own peak sales assumptions for nusinersen but mine are pretty generous. Nusinersen reaching $2 billion in peak sales would make it one of the most successful orphan-disease drugs ever developed. For perspective. Alexion's Soliris is expected to bring in $2.8 billion in sales this year.

I reject the popular idea amongst Ionis bulls that the company is "bashed" or picked on unfairly by skeptics. Ionis' market cap of $4.5 billion is remarkable for a company without a revenue-generating product. Only Alnylam Pharmaceuticals, an RNAi competitor also without any approved drugs, is valued higher by the market.

I happen to believe Ionis' pipeline is overvalued given the questions about the safety and tolerability of its technology platform. If you ask around Wall Street (and I have) you'll hear my concerns echoed by others.

Ionis can prove skeptics wrong, but it's going to take more positive (and clean) clinical data and approvals leading to meaningful sales.

Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.