Adverum Biotechnologies, Inc. (0HA3.L)

Here's the information that helped me with my decision, Philip's post 2 month ago (thanks Phil).
"I’m heavily vested in this industry. Hope this helps you make informed decisions:

Since ~2001 AntiVEGF compounds started being used to treat wet AMD, and then later, numerous other vascular and diabetic diseases of the retina.

Of these, Aflibercept (Eylea - regeneron) went on to hold the largest market share since it had the best durability, equivalent or superior effect, and equivalent or inferior complications.

When Brolizumab (Beovu - Novartis) was released it was expected to wipe out Eylea’s market share given it’s higher durability and great study results. But, on wide scale use patients developed inflammatory/vascular problems.. Now some of us suspect this is not related to the formulation of the compound but instead to the high molarity of the drug compared to all previous competitors at the time.

Interestingly, there are other high molarity Intravitreal drugs on the market that ran into the same inflammatory problems leading to vasculitis, hypotony, etc. (coincidence doesn’t make fact). Indeed, ADVM made this list having this issue with it’s high dose vector treatments for Diabetic retinopathy and it dropped that arm of it’s study as a result.

Now coming down the AntiVEGF pipeline multiple companies have created viral vectors that will make host cells produce AntiVEGF. Different companies hold different rights to the AntiVEGF the host cells produce. ADVM has the right to Aflibercept (Eylea). All other companies hold AntiVEGFs that maintain minimal dominance in the current intravitreal AntiVEGF industry.

The routes of viral vector delivery include intravitreal [ADVM], suprachoroidal, and subretinal. Currently, all AntiVEGF delivery is done intravitreal so ADVM has the delivery system that could go mainstream immediately. The other two would require additional training of the physicians, however, suprachoroidal is easy to learn. (Subretinal can only be done in the OR - thus excluding the entire medical retina specialist market)

To further complicate things, the amount/molarity of viral vector needed is greater in intravitreal and suprachoroidal injections compared to the [harder] subretinal injections. Thus, the risk of inflammatory issues may likely be greater in intravitreal and suprachoroidal injections compared to subretinal..? (This is the real question that needs to be pondered about ADVM)

Coming much later down another pharma pipeline is a sustained AntiVEGF delivery system through intravitreal pellet injection. Expected to last 6 months, twice that of current intravitreal injections. Additionally the pellet delivery system has a much easier road to success given its modality has already been proven successful in the intravitreal steroid market.

However, the viral vectors could potentially last forever or at least significantly reduce the intravitreal Injections needed in the future. If successful, their ability to program cells to make AntiVEGF indefinitely make any temporary sustained release pellet obsolete.

Endpoint:
If ADVM is truly having the success it claims with it’s viral vector system for Aflibercept in treating wet AMD (without inflammation!) - then there is a high probability it will dominant the industry given its ability to easily assimilate and provide cell production of a superior AntiVEGF. (This assumes the cells have appropriate production of aflibercept compared to competitor viral vectors - ADVM data makes this seem plausible..)

My concern is that the small sample size in data is hiding the potential inflammatory fallout on a large scale. Similar to what happened with brolizumab (beovu). But if successful, this is like buying regeneron when it was 15$, but it’s on a fire sale for 2$. It’s a gamble, no doubt.

Side note:
In capitalist America - money talks. Wet AMD is the most important and first market all AntiVEGF agents seek approval for.. because Medicare will pay for it. Diabetics, especially those in need, are often younger and may not be insured thus their large market size is difficult to capitalize on monetarily. I say this in reference to ADVM dropping its diabetic arm. Dropping the diabetic arm is essentially irrelevant if they deliver on wet AMD.

That being said, this viral vector technology has the most utility in the younger poor compliance diabetic population. In the future, those are the ones whose vision will truly be saved

I’m heavily vested in this industry. Hope this helps you make informed decisions:

Since ~2001 AntiVEGF compounds started being used to treat wet AMD, and then later, numerous other vascular and diabetic diseases of the retina.

Of these, Aflibercept (Eylea - regeneron) went on to hold the largest market share since it had the best durability, equivalent or superior effect, and equivalent or inferior complications.

When Brolizumab (Beovu - Novartis) was released it was expected to wipe out Eylea’s market share given it’s higher durability and great study results. But, on wide scale use patients developed inflammatory/vascular problems.. Now some of us suspect this is not related to the formulation of the compound but instead to the high molarity of the drug compared to all previous competitors at the time.

Interestingly, there are other high molarity Intravitreal drugs on the market that ran into the same inflammatory problems leading to vasculitis, hypotony, etc. (coincidence doesn’t make fact). Indeed, ADVM made this list having this issue with it’s high dose vector treatments for Diabetic retinopathy and it dropped that arm of it’s study as a result.

Now coming down the AntiVEGF pipeline multiple companies have created viral vectors that will make host cells produce AntiVEGF. Different companies hold different rights to the AntiVEGF the host cells produce. ADVM has the right to Aflibercept (Eylea). All other companies hold AntiVEGFs that maintain minimal dominance in the current intravitreal AntiVEGF industry.

The routes of viral vector delivery include intravitreal [ADVM], suprachoroidal, and subretinal. Currently, all AntiVEGF delivery is done intravitreal so ADVM has the delivery system that could go mainstream immediately. The other two would require additional training of the physicians, however, suprachoroidal is easy to learn. (Subretinal can only be done in the OR - thus excluding the entire medical retina specialist market)

To further complicate things, the amount/molarity of viral vector needed is greater in intravitreal and suprachoroidal injections compared to the [harder] subretinal injections. Thus, the risk of inflammatory issues may likely be greater in intravitreal and suprachoroidal injections compared to subretinal..? (This is the real question that needs to be pondered about ADVM)

Coming much later down another pharma pipeline is a sustained AntiVEGF delivery system through intravitreal pellet injection. Expected to last 6 months, twice that of current intravitreal injections. Additionally the pellet delivery system has a much easier road to success given its modality has already been proven successful in the intravitreal steroid market.

However, the viral vectors could potentially last forever or at least significantly reduce the intravitreal Injections needed in the future. If successful, their ability to program cells to make AntiVEGF indefinitely make any temporary sustained release pellet obsolete.

Endpoint:
If ADVM is truly having the success it claims with it’s viral vector system for Aflibercept in treating wet AMD (without inflammation!) - then there is a high probability it will dominant the industry given its ability to easily assimilate and provide cell production of a superior AntiVEGF. (This assumes the cells have appropriate production of aflibercept compared to competitor viral vectors - ADVM data makes this seem plausible..)

My concern is that the small sample size in data is hiding the potential inflammatory fallout on a large scale. Similar to what happened with brolizumab (beovu). But if successful, this is like buying regeneron when it was 15$, but it’s on a fire sale for 2$. It’s a gamble, no doubt.

Side note:
In capitalist America - money talks. Wet AMD is the most important and first market all AntiVEGF agents seek approval for.. because Medicare will pay for it. Diabetics, especially those in need, are often younger and may not be insured thus their large market size is difficult to capitalize on monetarily. I say this in reference to ADVM dropping its diabetic arm. Dropping the diabetic arm is essentially irrelevant if they deliver on wet AMD.

That being said, this viral vector technology has the most utility in the younger poor compliance diabetic population. In the future, those are the ones whose vision will truly be saved.

So frustrating to see that it is just irrationally to have these prices.... i am not an experienced investor, but ADVM:
1. felt down from 10 to 4 in APR because of the bad side effects of the DME treatment;
2. has 400M cash and 40M debt only; at burn rate of 100M per year - 4years ahead are safe;
3. has only 100M shares, i.e. cash per share is 4$ today;
4. the 3y low is just under 3$; seems like now, at 2.3$ we are now at a ATL price;
5. they still have a working product 022, in progress; they also have a sold licence (see pipeline on their web).

What do I miss ladies and gentlemen? I got tired of averaging down...

Novartis Beuvo Wet AMD Safety concerns:

On 23 February 2020, the American Society of Retina Specialists reported side effects of the drug, specifically in 14 cases of retinal vasculitis reported in Beovu patients, 11 of the cases were occlusive retinal vasculitis (that can lead to vision loss). Novartis responded with a statement standing behind the efficacy of Beovu.
On 11 June 2020, the FDA approved an updated Beovu label, that included additional safety information specifically including the characterization of adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation observed in HAWK and HARRIER clinical trials and noted in the original prescribing information.

"However, Beuvo was approved by FDA, and peak annual revenue is expected to reach $4B."

ADVM is back to $24. (Do your own DD)

Adverum Biotechnologies Granted Orphan Drug Designation by FDA for Gene Therapy Candidate in Preclinical Development for the Treatment of Blue Cone Monochromacy- ADVM-062 is designed as a potential treatment for blue cone monochromacy (X-linked incomplete achromatopsia)
REDWOOD CITY, Calif., Jan. 04, 2022 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc.(ADVM) , a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to ADVM-062 (AAV.7m8-L-opsin), a novel gene therapy product candidate being developed as a potential single intravitreal (IVT) administration for blue cone monochromacy (BCM) by delivering a functional copy of the OPN1LW gene.

“We are excited to introduce ADVM-062, which builds on our ophthalmology and gene therapy expertise to address the significant unmet medical needs of patients living with blue cone monochromacy. We are pleased the FDA has recognized the patient need by granting Orphan Drug Designation and we look forward to advancing ADVM-062 towards the clinic and generating important data,” stated Laurent Fischer, M.D., president and chief executive officer of Adverum Biotechnologies(ADVM).

BCM affects approximately 1 to 9 in 100,000 males, worldwide. This X-linked recessive hereditary condition is caused by mutations in either the L or the M opsin gene(s) and can manifest in loss of visual acuity, photophobia, myopia and infantile nystagmus that can persist into adulthood. Consequently, individuals with BCM have visual impairments to important aspects of daily living such as facial recognition, learning, reading, and daylight vision. Currently, there is no cure for BCM.

Orphan drug designation is granted by the FDA to novel drugs and biologics, which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits towards the cost of clinical trials and prescription drug user fee waivers. The orphan drug designation also could entitle Adverum Biotechnologies to a seven-year period of marketing exclusivity in the United States for ADVM-062 should the company receive FDA approval for the treatment of BCM for this product candidate.

Anticipated Milestones for ADVM-062

Plan to present preclinical data supporting proof of concept of ADVM-062 in 1H2022.
Plan to submit an Investigational New Drug (IND) application by year-end 2022.
About ADVM-062 Gene Therapy

ADVM-062 is a gene therapy candidate specifically designed to deliver a functional copy of the OPN1LW gene to the foveal cones of patients suffering from BCM via a single IVT injection. ADVM-062 utilizes Adverum’s propriety vector capsid, AAV.7m8