Can Intellia One-Up Alnylam In Transthyretin Amyloidosis? (NASDAQ:ALNY)



For years, sufferers with transthyretin amyloidosis (ATTR) have had restricted therapy choices. ATTR is a uncommon genetic illness the place a mutation within the TTR gene causes the liver to provide a misfolded protein known as transthyretin, which may construct up in physique tissues leading to polyneuropathy and cardiomyopathy. Today, there are a number of firms growing revolutionary remedies that maintain the potential to drastically enhance the standard of life for these sufferers. In this text, I’ll spotlight the race between Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY) and Intellia Therapeutics, Inc. (NASDAQ:NTLA) to develop the gold-standard in care.

Alnylam’s Success

On August 3, 2022, Alnylam Pharmaceuticals reported constructive topline outcomes from its a lot anticipated APOLLO-B Phase 3 trial of patisiran in sufferers with cardiomyopathy. While patisiran has already been authorized for sufferers with hereditary ATTR with polyneuropathy and has been wildly profitable with practically $550 million in trailing 12-month gross sales, the largest potential market is in ATTR sufferers with cardiomyopathy. The firm reported the APOLLO-B trial met its major endpoint with a statistically significant enchancment within the 6-minute stroll check in comparison with placebo at 12 months. The trial additionally met its first secondary endpoint in high quality of life as examined by the Kansas City Cardiomyopathy questionnaire, in comparison with placebo at 12 months.

APOLLO-B results

APOLLO-B Topline Results

ALNY knowledge by YCharts

The market rewarded Alnylam with a roughly 50% appreciation within the stock worth, which added round $10 billion to its market cap. While the complete set of knowledge (together with TTR knockdown) from the part 3 trial is anticipated to be introduced on the 18th International Symposium on Amyloidosis on September 8, 2022, the corporate has already introduced fairly a bit of knowledge from its HELIOS-A trial treating polyneuropathy sufferers. Alnylam has developed 2 separate RNAi therapeutics to deal with ATTR with the first era drug, patisiran, and the 2nd era formulation, vutrisiran. Both RNAi therapies work by silencing TTR gene expression, which straight reduces the circulating TTR protein.

Patisiran TTR knockdown

Patisiran TTR Knockdown (HELIOS-A Phase 3 Results)

As you may see from HELIOS-A trial, each patisiran and vutrisiran leads to a formidable TTR knockdown, which is sustained nicely previous the one-year mark. The discount within the misfolded TTR protein reduces and helps forestall further amyloid build-up in physique tissue. This research proved that lowering the circulating TTR leads to considerably improved medical outcomes. While we’ll have to attend till early September to get the official TTR knockdown from cardiomyopathy sufferers within the APOLLO-B trial, it is a logical assumption will probably be similar to the HELIOS-B (patisiran) knowledge above given the massive variety of sufferers dosed.

The TTR knockdown is particularly necessary in cardiomyopathy sufferers, as a result of this misfolded TTR protein continues to build up within the coronary heart which manifest as coronary heart failure and is usually not recognized till the affected person is presenting with superior phases of coronary heart failure. Alnylam proved with APOLLO-B that patisiran can efficiently deal with and enhance the lives of those sufferers with cardiomyopathy. However, Intellia can also be pursuing ATTR and needs to be presenting their part 1 knowledge in cardiomyopathy throughout the subsequent few months.


Intellia takes a barely totally different method than Alnylam to deal with ATTR. Intellia makes use of a lipid nanoparticle (LNP) as a supply mechanism to “knockout” the TTR gene with CRISPR/Cas9 and subsequently remove the poisonous protein manufacturing from circulation. The firm has launched spectacular, albeit, early knowledge in sufferers with polyneuropathy.

Intellia TTR

Intellia NTLA-2001 Knockdown (Corporate Overview August 2022)

Intellia has proven their NTLA-2001 remedy leads to a speedy and deep discount in TTR at day 28 and is sustained out to 12 months on the second lowest dose. Here is the place Intellia might be able to outperform Alnylam. Alnylam’s patisiran exhibits an preliminary steep TTR drop off however the TTR knockdown fluctuates within the 70-80% vary till round 9 months, when it then begins to see a gentle knockdown round 80%. Even 2nd era remedy, vutrisiran, does not see a sustained discount beneath 80% till week 36. Now, Alnylam has proven that its therapy does, in truth, considerably enhance affected person outcomes, however the query Intellia hopes to reply is whether or not a deeper and extra speedy discount supplies further profit. Remember, this misfolded circulating TTR protein can proceed to build-up or hinder amyloid clearance. Intellia administration believes this speedy discount may very well be key in treating sufferers with cardiomyopathy since it’s a progressively debilitating and deadly illness.

In the APOLLO-B knowledge, Alnylam did not meet a secondary endpoint (p-value 0.0574) of composite all-cause mortality, frequency of cardiovascular occasions and alter from baseline within the 6-minute stroll check. Alnylam administration believes it would seemingly meet this endpoint because the research progresses previous 12 months, but it surely does open a lane for Intellia to doubtlessly present its speedy and deeper TTR discount supplies higher medical outcomes, particularly in cardiomyopathy.

Intellia’s Path Forward

On the latest convention name, the corporate introduced all sufferers within the cardiomyopathy part 1 arm have been dosed and so they’ve chosen a hard and fast dose primarily based on the 0.7mg/kg knowledge they’ve seen. In addition, the corporate additionally disclosed that cardiomyopathy sufferers dosed at 0.7mg/kg and 1.0mg/kg have resulted in practically indistinguishable TTR knockdown ranges. The firm identified if the one outlier, who had lower than 80% knockdown, within the 0.7mg/kg polyneuropathy arm was eliminated that TTR knockdown was over 90% at that degree and that has been constant to what they’ve seen within the cardiomyopathy arm. Importantly, the cardiomyopathy arm has dosed 15 sufferers, so the corporate seemingly has knowledge on 3x extra sufferers on the 0.7mg/kg degree than within the polyneuropathy arm.

Intellia has introduced they may current knowledge from their NTLA-2001 cardiomyopathy arm within the 2nd half of 2022. It’s seemingly the cardiomyopathy knowledge Intellia presents will present a better than 90% knockdown of their most popular 0.7mg/kg dose. This speedy, deep discount is why administration believes NTLA-2001 has the potential to outperform each Alnylam’s each patisiran and vutrisiran. On the most recent convention name, Chief Medical Officer, David Lebwohl, acknowledged;

We’re seeing the Alnylam research type of as a wind to our again to determine all this out. We’re going to see the outcomes of that and assist us actually perceive what we have to do to see an consequence research. And once more, we now have this benefit that by getting deeper reductions, we are able to anticipate a greater end result than what they’re going to see with that – with any of the brokers as a result of none of them achieved the kind of TTR discount that we are able to obtain.


There’s little question, Alnylam is the present chief with their authorized therapeutic, patisiran, in ATTR – polyneuropathy and its seemingly approval for ATTR – cardiomyopathy. The newest constructive topline outcomes from the APOLLO-B trial assist de-risk the platform, as is clearly seen by the market’s response to the stock. However, Intellia is sizzling on their heels with the preliminary knowledge they’ve introduced. Since Alnylam has confirmed the discount in circulating TTR outcomes has improved medical outcomes, it causes to consider {that a} deeper and extra speedy discount in TTR, supplied by Intellia’s NTLA-2001, may yield further advantages, particularly in cardiomyopathy sufferers affected by coronary heart failure.

To be clear, Intellia nonetheless has a lot of inquiries to reply and is probably going 2-3 years behind Alnylam in getting NTLA-2001 to market. While early knowledge has been spectacular, Intellia nonetheless has not introduced medical enhancements for sufferers, which ought to come as the information progresses. In addition, Intellia has solely dosed 30 sufferers and introduced knowledge on 15 sufferers thus far. The firm wants to duplicate early success throughout a bigger affected person inhabitants, with the intention to rival Alnylam’s knowledge.

The upcoming knowledge launch by Intellia for sufferers with cardiomyopathy will probably be an enormous catalyst for the stock. If their cardiomyopathy knowledge mirrors their polyneuropathy knowledge (proven above), it units the stage for Intellia to doubtlessly one-up Alnylam with higher medical outcomes for these sufferers affected by superior phases of cardiomyopathy. It’s necessary to recollect it is a progressively deadly illness, so sufferers are determined for the very best remedy on the market.

Cash Burn & Risks

One main query for all biotech firms is their money readily available and money burn. Currently, Intellia is well-positioned with simply over $900 million in money, due to well-timed stock choices. Even with a quickly increasing pipeline, administration expects their present money steadiness will fund operations for no less than one other 24 months. However, traders ought to count on additional stock choices following constructive knowledge that leads to an appreciation in stock worth. The firm has utilized this technique prior to now and can seemingly achieve this going ahead.

Alnylam is a extra superior biotech with a mid-point income steerage for FY2022 of $900 million. An approval of patisiran in ATTR-cardiomyopathy would turbocharge this income, but it surely does should be mentioned that the corporate is at present dropping round $250 million per quarter as the corporate has quite a few superior medical trials requiring massive quantities of R&D. However, like Intellia, Alnylam is extraordinarily nicely positioned to maintain operations with over $2 billion in money. At present ranges, the corporate can fund operations nicely into 2024, however I’d count on the money burn to gradual considerably when patisiran will get approval for cardiomyopathy.

While these 2 shares are each lumped into the biotech sector, they’re at a lot totally different positions alongside their development trajectory. Alnylam has a number of authorized therapies bringing in income and with the constructive top-line leads to the APOLLO-B part 3 trial, they’ve largely de-risked the platform and are poised for speedy income development. The addressable market in ATTR-cardiomyopathy is round 3 instances the scale of polyneuropathy and as acknowledged above, Alnylam has earned round $550 million within the final 12 months from patisiran of their authorized polyneuropathy inhabitants. I consider the danger to Alnylam comes from Intellia’s potential superior remedy consuming into their income in ATTR. The market has assumed approval of patisiran in cardiomyopathy and added round $10 billion to their market cap in consequence. If Intellia exhibits a speedy TTR knockdown of 90% leads to improved affected person outcomes, Alnylam will lose its standing because the clear chief in ATTR.

Intellia has a way more unstable path ahead than Alnylam does. To date, Intellia has solely proven outcomes from a single part 1 trial. The danger to Intellia comes from a possible stumble in medical outcomes or security issues from their remedies. While Intellia is nicely off their 2021 highs of $180/share, it may fall a lot additional if issues of safety creep up. However, the upside potential within the stock is way larger from present ranges.


At this level, Alnylam is the most secure decide within the area, however Intellia has the potential to be a best-in-class remedy with large upside. These shares seemingly appeal to traders with a lot totally different funding methods. Alnylam has confirmed therapies and a big pipeline of promising therapies. At round $215/share, Alnylam is a superb stock to purchase and maintain and benefit from the development as their massive pipeline continues to translate into income.

Intellia is a high-risk, high-reward stock at present ranges underneath $60/share. A downturn within the market, particularly within the early-stage biotech trade has left the stock down 50% YTD. However, the corporate is nicely capitalized and has a lot of necessary catalysts within the subsequent a number of months. A constructive knowledge launch in cardiomyopathy would seemingly propel the stock worth to the following degree of resistance round $75/share. It may go larger, however traders ought to keep in mind that is nonetheless a part 1 trial and medical outcomes won’t be introduced, solely efficacy and security knowledge. Investors trying to set up a place in Intellia needs to be comfy with volatility as there are numerous questions left to be answered.

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