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EDITED TRANSCRIPTALNY - Alnylam Pharmaceuticals Inc RNAi Roundtable: ALN-AT3 forthe treatment of Hemophilia and Rare Bleeding Disorders

EVENT DATE/TIME: JULY 22, 2015 / 1:00PM GMT

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C O R P O R A T E P A R T I C I P A N T S

Josh Brodsky Alnylam Pharmaceuticals Inc. - Senior Manager, IR and Corporate Communications

John Maraganore Alnylam Pharmaceuticals Inc. - CEO

Margaret Ragni University of Pittsburgh - Professor of Medicine & Director, Hemophilia Center of Western Pennsylvania

Mark Skinner World Federation Of Hemophilia/National Hemophilia Foundation - Past President

Benny Sorensen Alnylam Pharmaceuticals Inc. - Senior Director, Clinical Development

P R E S E N T A T I O N

Operator

Thank you, ladies and gentlemen, for joining today's RNAi Roundtable. We will be conducting two web-based question-and-answer sessions duringthe webcast. You may submit a question at any time during today's presentation by clicking the Ask a Question button located above the slidewindow on the webcast player.

I would now like to turn the call over to Josh Brodsky for opening remarks. Josh, you may proceed.

Josh Brodsky - Alnylam Pharmaceuticals Inc. - Senior Manager, IR and Corporate Communications

Good morning, everyone, and thank you for joining us for our RNAi Roundtable to discuss the progress we are making with ALN-AT3 in developmentfor the treatment of hemophilia and rare bleeding disorders. I am Josh Brodsky, Senior Manager of Investor Relations and Corporate Communicationsat Alnylam.

With me today are John Maraganore, our Chief Executive Officer; Dr. Margaret Ragni of the University of Pittsburgh and Hemophilia Center ofWestern Pennsylvania; Mark Skinner, past President of the World Federation of Hemophilia and National Hemophilia Foundation; and Dr. BennySorensen, Senior Director of Clinical Development at Alnylam.

I will be turning it over to John shortly, who will provide you with a brief introduction, but first a few comments. Our RNAi Roundtable today focusedon hemophilia and rare bleeding disorders kicks off a series of roundtables that we are hosting this July, August, and September. Today's eventwill end at around 10:30 AM Eastern Time.

We will be taking questions from you via the webcast and you can submit a question at any time during the event by clicking the Ask a Questionbutton located above the slide window on the webcast player. John will moderate a Q&A session with both Dr. Ragni and Mr. Skinner, and thenwith Benny at the conclusion of each of their presentations.

As a reminder, we will be making forward-looking statements and we encourage you to read our most recent SEC filings for a more completediscussion of risk factors. And with that, I will turn it over to John.

John Maraganore - Alnylam Pharmaceuticals Inc. - CEO

Thanks, Josh. Good morning, everybody. Very excited to be moderating the first of our summer RNAi Roundtables. It is especially exciting to meto be moderating our session on ALN-AT3 because I am a former clotter, for one. That's one reason. But, importantly, it is a drug that -- a medicinethat we believe to be truly innovative and potentially disruptive and make a big difference in patients' lives.

Now before we dive in, I want to just make a few introductory comments for some overall content. As you know, Alnylam has built over the lastseveral years a really exciting platform. It is a reproducible and modular platform for innovative medicines based on RNAi therapeutics, and ourapproach with RNAi therapeutics has been to target disease genes expressed in the liver that are genetically validated.

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JULY 22, 2015 / 1:00PM, ALNY - Alnylam Pharmaceuticals Inc RNAi Roundtable: ALN-AT3 for the treatmentof Hemophilia and Rare Bleeding Disorders



Our R&D strategy, as you probably know, has been focused on programs where there is an opportunity for an early proof-of-concept readout andalso a definable path to regulatory approval and market access. And in many regards, of course, ALN-AT3 really fulfills all of these criteria.

Antithrombin is genetically validated. There's also genetics around the co-inheritance of antithrombin deficiency in hemophilia. Of course, thereare early proof-of-concept data that can be read out in early clinical studies, and there is in fact, as Benny will go through later on today, a verydefinable path to a regulatory approval.

So let's now turn to the next slide, slide 6. And this slide just is here to remind all of you that today Alnylam is really building and exciting pipelinewith seven clinical-stage programs, two of which are in Phase 3. Clinical studies across our three strategic therapeutic areas, or STArs.

Now turn to slide 7. Of course, today's focus is on ALN-AT3, which is currently in an ongoing Phase 1 study where we will present today or updateyou today on some of our data from that study, but which we expect to be a Phase 3 in middle of 2016. Now with that as introductory comments;turning to slide 8 let me now introduce our two external speakers.

We have a great pleasure to have both Dr. Ragni, Maggie, and Mark with us today. It's really a pleasure that they can commit the time to thisdiscussion. Maggie will give us an overview of the hemophilia disease setting and the current treatment landscape and Mark will give us the patientperspective on this bleeding disorder.

After Maggie and Mark make their remarks and go through their slides, we will then do a Q&A. So with that, let me turn it over to Maggie. Maggie?

Margaret Ragni - University of Pittsburgh - Professor of Medicine & Director, Hemophilia Center of Western Pennsylvania

Good morning. Thank you for allowing me to talk with you this morning. My goal in this talk is really to give you an overview of hemophilia and alittle bit about the disease, the treatment, and where some of the gaps in care exist.

I would have to start out by saying this is an exciting time for hemophilia with the development of many new technologies that are going to targetvarious pathways and proteins in the coagulation pathway to improve hemostasis. Hemophilia is an X-linked disease that affects 400,000 worldwide.It's caused by a deficiency of coagulation factor VIII, which we call hemophilia A and which accounts for 85% of the disease, or factor IX, which isthe cause -- the deficiency is the cause of hemophilia B, accounting for about 15% of the disease.

And that, of course, was recently confirmed as the cause of the disease that Queen Victoria and her family had. She is, of course, the most famouscarrier. You see her here with her grandson, Prince Alexis, who was the first royal with the disease.

On the next slide, by way of historical background, you can see in the United States the first case was noted in 1803 and the first treatments werereally just a plain blood transfusion starting in 1840. And we have progressed, once we defined the disorder as a deficiency of factor VIII or IX inthe 1930s, to plasma; then to cryoprecipitate, which was a cold precipitate of plasma allowing factor VIII to be given more simply.

Then clotting factors were developed in the 1960s and 1970s and, of course, they had many complications including HIV and hepatitis C, whichare no longer problems with these clotting factors because they are all now recombinant clotting factors. And with the cloning of factor VIII andIX in the 1980s, those recombinant factors became a reality.

What has really been happening in the last few years, just approved by the FDA, are extended half-life proteins, which I will talk just a little bit aboutbecause they are the newest technology and a standard by which any new therapy probably would be looked at.

So on the next slide, slide 11, we are just showing you that hemophilia A and B are genes, are inherited as genes from the X chromosome -- Xq28for hemophilia A, Xq27 for hemophilia B. The incidence is about 1 in 5,000 male births for hemophilia A and 1 in 50,000 for hemophilia B.

Their lifespan is now normal and that is because there is no new HIV and hepatitis C. So they are living longer lives; we are looking for bettertherapies to make better quality of life. And if you look at racial distribution, it is just as you would see in a country today.

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Now on the next slide, it's a bit of a busy technical slide, but really in red you see where factor IX falls in the coagulation cascade and in blue wherefactor VIII falls. And if those factors are deficient, which they are in the hemophilia, you cannot make a normal clot, which is actually thrombin, orIIa, which you see close to the bottom of the screen. That then results in uncontrolled bleeding and that is the cause of the morbidity of the disease.It can be either spontaneous or traumatic bleeding, depending on the severity of the disease, but it's managing that deficiency that is the focus ofthis disease.

Now how do these patients present? Of course, their number one problem is bleeding into joints, hemarthroses; or muscles, hematomas; andcertainly at birth circumcision bleeding.

As you can see, Prince Alexis over there on the right had all of his royal portraits taken with his left leg on a step behind him because he had asevere hemarthrosis. And you can see how disabling it might be if you could not completely straighten your leg, but moreover, more importantly,a lot of pain, disability, quality-of-life interference with activities of daily life.

So really with the disease, which is a disease of spontaneous and traumatic bleeds, it's really critical to try to treat or prevent those bleeds. That isthe focus of management. However, the current standards are very costly with up to several thousand dollars per treatment. They are invasive.You have to use an IV to do them.

We have many patients who learn how to do this, but as you will see in a few slides, over half the adults do not want to follow that standard of IVtherapy several times a week. And, moreover, the factor is immunogenic. Up to 25% of children after their first 20 doses or so will develop aninhibitor, making treatment even that much worse, which we also talk about.

So what's novel are some of the new approaches to trying to either prevent inhibitors or these EHL, that is extended half-life proteins. But you aregoing to see that these are not perfect and there are still going to be gaps in care, even with these new extended half-life proteins which I will showyou.

So on the next slide, just by way of background, what is a hemophilic joint? That is a hemarthrosis. It is really a joint that has recurrent bleeding.

The blood sets up an inflammatory response, activates various different cytokines and tissue factor, and the persistent recurrent bleeding causesiron deposition in the joint. There is loss of that nice synovial lining that allows wonderful movement for the normal individual, but in the patientwith hemophilia there's iron deposition.

There's death or apoptosis of the chondrocytes; that is the cells that line the joint. And, in fact, what we see is a disease that looks like RA, rheumatoidarthritis, with degenerative joint disease, or DJD, but occurs in children. So you can see that these people have morbidities that start in their 20sthat require surgery in their 30s and 40s and cause a lot of problems.

One of the questions is can you prevent this? So we are going to talk a little bit about prophylaxis; can prophylaxis prevent joint disease? Beforewe do, I just want to make a couple points.

In order to treat a patient with hemophilia, it's critical to have early accurate diagnosis and we have a number of hemophilia centers across thecountry, over 140, where this happens every day. New patients are diagnosed. I think you should notice that up to 30% have spontaneous mutations,so this is a disease that is continuing the population.

Early adequate factor treatment is the sine qua non for treating these patients. However, I would note that that is reactive; waiting till the bleedoccurs. It is invasive; you have to put in an IV. And, moreover, for the world it's really not a reality because it's too expensive for most third worldcountries.

In the countries that do have the product what we try to do is prophylaxis; that is prevent bleeds before they occur, but this requires giving IVsbefore a joint bleed occurs. You can imagine being ready to put an IV in if you are having pain and swelling, but without the pain and swelling you

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might ask yourself do I really need to do this? And, in fact, more than 50% of adults say that and don't want to do that, and it makes for a continuingmorbidity of disease. Major gap in the public health management of this disorder.

As I have already mentioned, inhibitors, that is proteins that the immune system makes when it sees the foreign-infused factor VII because it'sdifferent from what they have or have very little of, sets up this immune response that prevents them from responding to standard factor VIII. Soan inhibitor patient, which in factor VIII deficiency occurs in about 25% of the patients, is a major deterrent to managing the patient. And they havemuch greater morbidity, twice the cost and times the hospitalizations, and over 70% higher morbidity or mortality.

I would like to just very briefly talk about, as you can see on slide 16, four complications: joint disease, inhibitor formation, the effects of HIV andhepatitis C, and the existence of another coagulopathy in a patient with hemophilia, which can make their disease that much more difficult tomanage.

So prophylaxis. This is a bit of a busy slide, slide 17, but this is actually taken from a landmark randomized clinical trial that was published in theNew England Journal in 2007 by MancoJohnson et al. And what it showed was that in young children using prophylaxis, that is preventive treatment,up to 3 times a week before they started having bleeds resulted in joint damage prevention and prevention of bleeds.

You can see in yellow there were no joints that were damaged in up to 93% of those on prophylaxis as compared with 55% in these young children,and there were no joint bleeds or fewer joint bleeds by far in those receiving prophylaxis compared to those with standard therapy, which is justwait till the bleed occurs. And so this is what sort of set the tone and provided the evidence-based approach to using prophylaxis in patients withhemophilia.

In fact, the recommendations, as you can see on the next slide, are to begin early treatment -- that is with the very first bleed -- to reduce jointdisease pain and disability. And of course, the issues there have to do with compliance; the frequency of injections, which is about 3 times a week;the invasiveness; and of course the cost of this, which is, as I mentioned, several thousand dollars per treatment, several hundred thousand dollarsper year if you estimate that they have three to four bleeds in a month's time if they don't use prophylaxis.

But despite how effective this paper showed that prophylaxis is fewer than 50% will follow it, and so you can see this is a major gap in care. Thesecond problem I want to talk about on the next slide is inhibitor formation. This is the leading complication of hemophilia.

It results because the patient no longer can respond to infused factor VIII; that there's this protein being developed in their immune system thatreacts with infused factor VIII. They have uncontrolled hemorrhages. They are unresponsive to factor VIII. We know how to diagnose these, but it'svery difficult.

We don't know how to prevent them and we certainly have a lot of trouble treating them. We know that you can eradicate the inhibitor by usingwhat we call immune tolerance. That's very high dose factor on a daily basis, which you can imagine is extraordinarily difficult in the children inwhom this occurs.

We often have to use ports placement to do very difficult daily treatments, which are really difficult and complicated by infections and sepsis. Andthen we also -- that doesn't have anything to do with stopping the bleeding, which is the second approach to treatment, and we have to use whatwe call bypass treatment, which is really not as effective as factor VIII is in a patient who doesn't have an inhibitor.

So these patients have severe morbidity, twice the cost, 10 times the hospitalizations and 70% higher death rate. This is a very difficult diseasewhich has led many to think about how could we prevent it. I'm just giving you on the next slide, slide 20, just a little look in one slide at some ofthe things we're thinking about.

On the left you see a graph which is from a paper by Gouw, who did one of the absolutely most -- one of the best papers I've ever seen, of over 400children before they had their first bleed. They started factor and showed that within 20 to 30 treatments 28%, or about a quarter, of them developedinhibitors.

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So these are -- as I'm showing you, they cause such disability that we want to prevent them rather than try to treat them. There are a couple theorieson how one might do that: start treating before you ever have a bleed and a very low dose approach to sort of reduce this danger theory ofhigh-intensity treatment with bad bleeds. This is very difficult to do in children.

The other part of that is to use something that causes a prolonged half-life and, in fact, there are a number of very interesting animal studies, whichI will not go into, that suggest that the extended half-life proteins have a tolerizing. They actually induce what we call regulatory T cells that actuallyinduce tolerance to the infused factor VIII.

This is interesting because what is that related to? Is it the prolonged time that the factor is present? And what might this -- what does this portendfor new or other new novel prohemostatic agents. So anything that could make a dent in the treatment, in the gaps that cause problems with --for hemophilia inhibitor patients would be extraordinarily welcomed.

Now the third problem I wanted to just briefly touch on was hepatitis C and HIV. You can see an orange on our little timescale on the bottom youcan see where hepatitis C was causing new hep C infection in our patients with pedophilia and HIV infection, which was just in the middle of that.

And what you are really seeing is until they have their combined modalities of antiviral therapy, these were devastating diseases for the patients.And while there are no new infection with HIV or hepatitis C, this is a major cause of morbidity and mortality in patients with hemophilia who arenow adults today. So this is something that we clearly look at; not just we, but our patients are very sensitive to any new therapy in their treatmentregimens.

What are the risks? They are not going to go through the HIV and hepatitis C era again. And while we have wonderful treatments these days, thereare complications to those treatments which again is not the focus of this talk, but it just underscores other gaps in the care of these patients.

They have many, many problems. If you are an adult today and you have severe hemophilia A or B, you have these problems and they are a partof your lifestyle. They do affect your quality of life as well as your longevity.

And then, finally, I just wanted to also talk on slide 22 about the confounders of hemostasis. What I mean is there are different situations that canmake your bleeding worse or make your bleeding less severe, but you really need to be aware of these things because, unless you are, you maydie of your disease.

The type of hemophilia is critically important. If you have hemophilia A, we know by a number of hemophilia severity scores that your disease ismuch worse than if you have hemophilia B, even though it was always touted that these were identical diseases. They clearly are not. You havemore joint disease, more hospitalization, higher cost, and more treatments required if you have hemophilia A.

What about coexistent thrombophilia? In other words, disorders that cause you to be at risk for clotting, deep venous thrombosis? Well, it turnsout those disorders, if you also have hemophilia, have a more stabilizing effect and in fact is the basis for looking at such proteins as antithrombinIII. And you are going to hear a lot more about it.

So these are very exciting findings in hemophilia that also have thrombophilia that really lay open the ideas for approaches that are really novel,such as ALN-AT3.

If you have a coexistent, a hemostatic disorder, number three, you are going to have more bleeding. And if you don't recognize that that is present,you may die from your bleeding even if we treat your underlying hemophilia.

Finally, thrombocytopenia, which means low platelets. Certainly many of our patients that develop liver disease, if they are not cognizant of thefact, their doctors or they, that they have low platelets, they can bleed from severe low platelets that no matter how much we treat their hemophiliamay not be sufficient unless given in a high enough dose and great enough frequency to thwart those bleeding problems, especially centralnervous system bleeding.

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So we're on to treatment. What's new? And so I would really like to sort of help you with where we are today; what we have as new therapies, theextended half-life; and then where some of the new exciting therapies are going to take us and then turn it over to Mark.

On this slide, slide 24, we are talking about what is the standard therapy for patients with hemophilia today? On the left is factor VIII deficiency orhemophilia A. On the right is factor IX deficiency or hemophilia B.

What you are seeing is we use factor VIII at a dose of 50 units per kilogram. This is a recombinant factor VIII. It's given by intravenous therapy andit's dosed on the half-life, which is about every 8 to 12 hours, which results in a requirement for about 2 to 3 times weekly if you want to preventyour bleeds. Now this doesn't also address trauma, which, if you have that in addition, will require even more treatment.

For factor IX the dosing is about 75 to 100 units per kilogram. With a half-life of 12 to 24 hours, you can get by with once to twice weekly dosing,and if you have trauma, additional dosing. As you can see, this is a very intense, invasive, laborious approach to therapy.

Monitoring; we clearly have coagulation tests and can do that. We routinely monitor for inhibitors and we also have an approach to treatinginhibitors, as we have already talked about.

On the next slide, slide 25, you are going to see what we have new today. In 2014, the FDA approved two extended half-life proteins. One was afactor IX Fc fusion protein, Aprolix, which you can see in the left, and a factor VIII Fc fusion protein factor VIII, which is Eloctate.

Basically these are -- I'm not promoting those drugs; I'm telling you they are the first ones approved in this line of treatment. There are new onescoming out that will be fusion products with albumin and there are new ones coming out that will be PEGylated proteins, sort of like the way theinterferon for hepatitis C is a PEGylated protein.

What these do is prolong the half-life by various different mechanisms. And what you are looking at on the left in gray is what the standard half-lifeis for factor IX and in red how you can improve that half-life when you use an extended half-life protein. So rather than treating twice a week toprevent bleeds you can actually treat once a week and improve some of these products even up to once every two weeks with factor IX.

Not quite so good for factor VIII. We can you see in gray the half-life for factor VIII on the right and in dark black the half-life for factor VIII that's thefusion protein or the extended half-life protein. And what you can do there then is instead of three times weekly infusions you can go down totwice weekly infusions.

So it's exciting; it, perhaps, will be improving quality of life. There are many parameters that we really need to do good prospective studies on. Howmuch better are your joints? What's the impact of these new drugs? Do they truly reduce treatment in the standard setting, not just in a clinicaltrial?

How will the cost impact its use? How will it impact treatment of other disorders that patients are getting as they age, such as cardiovascular disease,requiring antiplatelet therapies and all those sorts of things? But what I am saying to you is this is a really exciting step and a forward projection,but it's not solving all the problems because it's still quite invasive.

Now on my final slide on slide 26, what I'm showing you is a little cartoon and I wish it was animated, but it is not. It is a wonderful slide by Versteegin 2013 in his excellent paper. I use it as a cartoon to talk about sort of the two novel approaches to design of prohemostatic agents today.

One is to inhibit the coagulation inhibitors. You can imagine that if you get rid of an inhibitor -- and in this cartoon for example look at the littleblue dots which are antithrombin. If you can knock it down or get rid of it you can prevent the breakdown of the clotting factor and allow it to havea prolonged half-life, which is an exciting, novel approach.

You can do that also by inhibiting TFPI, which is tissue factor pathway inhibitor, and as you can look here and see these will prevent the rapidbreakdown of factors IX and X or VII and X. And, again, a way to promote hemostasis and longer survival of fibrin and -- thrombin and fibrin clotonce they are made.

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So second approach is mutating coagulation factors so they are no longer sensitive to those coagulation inhibitors. And I'm giving you threeexamples here: a factor Xa that is mutated; a super factor Va, which takes advantage of mutations in factor V; and a mutated factor VIII, which is nolonger sensitive to standard cleavage.

So what I am saying to you is there are a number of very exciting approaches coming forward in Phase 1 and 2 trials. They were presented at theASH meeting at ISTH. We look at those. Every time we go to a meeting I rapidly pick up a journal because these are the places where I think there'spromise.

Clearly, we're going to need prospective clinical trials. We're going to need to look at the impact of cost, of what is the patient acceptability of thesenew novel therapies. And interesting questions: if you go from an IV to a subcu dosing, how does that feel?

I think there are a number of very exciting questions, but I do believe this is a very interesting collaboration between not only the physicians andthe scientists but the patients whose lives will be affected by what novel treatments come out, their safety, their efficacy, their cost. And so that'swhy it is timely for me now to turn the podium over to Mark Skinner, who is going to do the talk on patient perspectives. Mark?

Mark Skinner - World Federation Of Hemophilia/National Hemophilia Foundation - Past President

Good morning and thank you for that segue. It really is a pleasure to be here today and I very much appreciate the opportunity to offer apatient-focused perspective. Patient-centered care today is the mantra in about anything that you read, so the inclusion of the patient perspectiveas we think about clinical development I think is particularly important.

If we moved to slide 29, most talks that I give about hemophilia I start in 1960 because it's the year I was born. There's no other real magic aboutit. But if you do the math, I'm 54, soon to be 55 years old, and at the time I was born in 1960 my life expectancy would have been somewhere inthe mid 20s.

The pictures that you see here of the two young boys really were my reality as a child. I was treated with whole blood. I was treated with freshplasma. We kept an IV pole in my bedroom at home and by the time I was four years old I was in traction and wearing a brace on my leg andrequiring a wheelchair or crutches to get around.

Fortunately, I was born in the US and care has rapidly advanced. And I'm going to share with you a little bit about care here in the US, but also offersome perspectives of how some of these novel therapies might have the opportunity, be disruptive technologies globally, and really bridge anenormous treatment gap.

So shifting to slide 20 (sic), hemophilia was referred to as the lonesomest disease in this Saturday Evening Post article. And I find this somewhatremarkable because, if you look down in the right-hand corner of this slide, this actually is a letter that my grandmother wrote to the editor of theSaturday Evening Post right about the time my mom was expecting me.

My older brother, who also has hemophilia, was diagnosed about the age of two and her source of information to learn about hemophilia wasactually the Saturday Evening Post. And, remarkably, the Post wrote a letter back and directed her to the National Hemophilia Foundation, whichin fact I had the privilege to serve as president of a little over a decade ago.

Shifting to slide 31, the development of care in the United States, Maggie already mentioned some of the clinical developments and the US reallyhas been incredibly fortunate. We have had a national patient organization and later the world federation was established in 1963, and that wasmy reality when I was born.

The organization of patients, it was relatively lonely. I didn't know anybody else other than my brother with hemophilia until I was well into myteenage years and care rapidly advanced. As you might surmise from Maggie's comments, I was impacted by HIV and hep C. I still live with HIVand, fortunately, due to the advancements in modern medicine, my hep C was cleared last year, but these continue to be significant challengesfor patients in other parts of the world that don't have access to the modern therapies and are still relying on plasma and blood-based therapies.

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We can certainly rapidly move forward through the 1990s and the 2000s, and we are at an age where it is truly exciting. Patients that have accessto modern medicine and healthcare systems are seeing true revolutions from having to face the prospect of early death and significant morbidityand disability to the opportunity to live a completely full and normal life.

My great nephew, who is now seven, really should see none of the kinds of limitations that I have experienced. It has only been within the last 10years that I've had the ability to actually live my life fully and freely without the aid of crutches and canes because of the ability to do surgery andhave my knees and my ankles replaced or surgically corrected.

Shifting to slide 32, this really is what the reality of the world. Maggie mentioned that there is about 400,000 patients of hemophilia in the world.Three out of four patients living with hemophilia, in fact, don't have access to modern care or adequate treatment. They really are dependent uponwhat therapies similar to what I experienced as a child in the 1960s here in the US, and so my reality is, in fact -- as a child is still, in fact, the realityfor the vast majority of patients in the world today.

As you skip forward to slide 33, it becomes even more acute. And as you would expect, based on some of the cost estimates that Maggie mentioned,the disparity in care is particularly acute in low income countries. Just by way of example, only about 9% of the patients diagnosed worldwidecome from countries with a GNI of less than $1,500 and this group represents over a third of the world's population. So there's a significant needand opportunity to reach out.

On the next slide I highlight the disparity in factor VIII consumption. I live with hemophilia A, which is the deficiency in factor VIII protein, and ifyou just focus on the red and the gold triangles in these two pie charts, you will see that North America and Europe represent only about 15% ofthe world's population, yet in fact we consume 75% of the treatment products.

So these new therapies I believe hold great promise, whether it's the one we're talking about today or some of the others that Maggie mentioned,to really address the green, the purple, and the blue parts of the world as well as to advance the quality of life and outcomes for those of us thatlive in the more developed countries.

Slide 35 is really what my life is about today. As a patient, care is delivered in an integrated or comprehensive care manner where a multidisciplinarycare team really surrounds the patient to deliver all of the different skills. We have highlighted that it is disease with significant morbidity into thejoints, so the role of physical therapists and orthopedists is critically important. But it really impacts all other aspects of your life, whether it's dentalcare or even the psychosocial aspects and the ability to get a job, get an education, and to have a social life and a family.

We are highly dependent upon a care team which is a significant and expensive system, but as we showed in the history before, there's a networkof hemophilia treatment centers in the US that have been developed. And the World Federation of Hemophilia is promoting the development ofin other parts of the world that help meet that need, because we do know that if we intervene with the right care team, even in the absence orwith limited factor, we can improve survival. It doesn't necessarily improve morbidity, but we can improve survival. So the goal really is how canwe bridge that gap and get the treatment products that really will advance care to where we are today?

On slide 36, the data seems to indicate -- and I shouldn't say seems to indicate, it clearly indicates that about 90% of the cost of hemophilia caretoday is, in fact, product cost. And that is -- this is in the United States and most of Western Europe and that really is driven by the cost of treatment.The other 10% is consumed by all of the other costs including the care team. And we can't ignore that 10% because both parts are critical, but ifwe can do something about the 90%, we truly will have the opportunity to open up the world to access.

Shifting to slide 37, I'd like to think of the telecommunications industry as an example of what could happen in hemophilia. We really are lookingto some of the novel therapies to be truly disruptive technologies that can bridge that gap. Many countries in the world have completely skippedfrom no telecommunications system to cell phones and not had to go through those intermediate steps of stringing land lines across the countryto connect the world.

And our scenario, we are connected to healthcare through our comprehensive hemophilia treatment centers. And while they will remainfundamentally important, the whole healthcare infrastructure that is required to maintain a disciplinary team of four or eight healthcare professionals

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to support one patient may well change as we advance therapy. This, in addition to the potential cost savings with new products coming to market,has the opportunity to significantly alter the landscape of hemophilia that makes it not only more affordable but more accessible for patients.

If you live in a rural part of the country and your only expertise in hemophilia is in the capital city, which is typically the case in most of the emergingand developing world, you can imagine that they don't even have access to the basic integrated care team that's going to improve the mortalityin hemophilia, let alone the morbidity. So we see significant opportunities for progress in the long-lasting or extended half-life products that Maggietalked about; gene transfer technology is coming along well, but probably still a decade away; and then the more novel therapies that were justhighlighted in Maggie's last couple slides.

Then shifting to my last slide, 38, there really is still a gap in normal. As wonderful as my life has become, from spending a life in bed tethered toan IV pole and the significant disability that I experienced as a child; today, because I have been fortunate to live in the US, have access to qualityhealth care and insurance reimbursement, my life is approaching normal but it really isn't completely normal.

There still are significant burdens of living with hemophilia. I do have to think about what I do day in and day out. I have to plan physical activitiesand sports around what is the therapeutic benefit of the prophylaxis that I'm on.

I had to carefully pick my work and career that I didn't pick a physically demanding career and planned an education that would allow me to havea desk job early on. It certainly affects family and social life, and even more if you are living with the viral infections, so the ability to free up patientsfrom having many of these worries is still the goal. Prophylaxis is still an intervention that is trying to achieve a state of normal, but it has itslimitations.

So as we think about outcomes that are important to patients, while we want to reduce bleeding and we want to improve the quality of life, thekinds of things that I think of in terms of outcome and the kind of things that I discuss with my friends around the world are really: do you have theopportunity to get an education, get a job, have a family, and support your family, and live a quality of life that would be equivalent to your peersthat don't?

In fact, looking at my last slide, I think it truly is the case that hemophilia today can be manageable, but they were enormous gaps. And we arelooking to the new technologies to help us bridge that.

The young man on the right in the picture is in fact Alex Dowsett. Some of you may have heard about him in the news. He lives with severehemophilia. He is from the UK. He just was prominent in the Tour de France; he was a time trial winner and holds the world record in time trials inprofessional cycling. So what a remarkable difference his life is compared to what mine was as a child and what my nephew's will be in the decadesahead.

Thank you for the opportunity to share this with you.


Thank you very much, Mark. Great overview. We will now open it up for Q&A with Dr. Ragni and Mr. Skinner. And just as a reminder to those listening,you can still submit your questions by clicking the Ask a Question button that is located above the slide window on the webcast player. So pleasego ahead, John.

Q U E S T I O N S A N D A N S W E R S


Good. First of all, again, thanks, Maggie and Mark. I thought those were great overviews, very helpful. We do have (technical difficulty) here that Ithought it would be great to ask. And I think, Maggie, maybe starting with you and then switching to you, Mark, in the same question.

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Question is: what would make a physician decide or a patient decide to switch their current therapy? Maybe Maggie, let's ask you first. What wouldmake a physician decide to recommend a difference in therapy with some of these newer agents that emerge?


I think most physicians, whether they care for hemophilia or any other disease, are very, very careful. And in that regard I am talking about theywant to see evidence-based recommendations, number one. They want to see randomized controlled trials, if that's possible, or at least Phase 3trials in which there has been a careful assessment of safety, of efficacy, of what were the adverse events. How many patients developed inhibitors?Is it worse than what I already have?

I think both patients and physicians are cautious, and I think it may be even more so the case in this population for the simple reason they havealready had HIV and hepatitis C, which, thank goodness, is no longer affecting our population in new infections. But I actually also think peopleare very, very sensitive to cost and economic issues.

And I think people are thinking more globally. Is this something that could truly be used in third world countries where there are no products? Andis it simple enough that folks are really going to use it to make a major difference in their lives? In other words, is this an IV therapy that I have togive three times a week or is it a single oral dose that's safe, cheap, effective, and available worldwide?

I think those are the back of our heads, but quite frankly, the critical key there I think is where's the evidence? Is it safe? Is it effective? How does itwork in the real world after I get out of a clinical trial or after the clinical trial is done? Where is the data to show the impact and is the cost justified?Is whatever I have to do, if it's a subcutaneous injection under the skin, is that worth whatever this is going to do?

And, honestly, better treatment for a patient with an inhibitor would be a slamdunk because it's so bad right now. I mean personally I believe thatthat is an issue. I think if you can get -- reduce the frequency of treatment for any patient, and if you can avoid intravenous therapies, that is thebiggest -- really the biggest holdup in patients starting those therapies. And what holds people back from doing things that everyone else does:sports, Tour de France, or whatever it is.


That's great, Maggie. Mark, what about the patient perspective on that? What is -- is it different than what Maggie said or similar, or is there somethingelse that you would add?


I think it's very similar to what Maggie said. There will be early adopters in any technology, but I think we are an inherently cautious community,particularly in the countries that really felt the brunt of the HIV and hepatitis epidemics.

I think the decisions will be very personal and individual, and in fact, that really is the way healthcare is moving. So it will be a personalized decisionbetween the patient and their clinician; what's right for them.

I think one of the challenges we have to overcome; as patients we have thought about limitations of things that we can't do, and there is a mentalshift that patients are going to have to make as the new therapies come to market that, in fact, perhaps you can redefine your life goals and perhapsyou can redefine the opportunities that are available to you. The treatment doesn't have to be as burdensome and perhaps you can have greaterclinical efficacy and have more freedom in your life.

And those things won't happen overnight. They're going to have to be demonstrated to the patient. So I do think it will be a balance in howburdensome is the treatment to adopt early versus am I not being able to accomplish the goals that I've set for my life and will this treatment helpme do that? So it will happen.

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Cost is a significant barrier. The Affordable Care Act has eased that some in the US, but there are still enormous challenges and there's enormouspayor pushback. And I don't think we can assume that even the care that we have today won't go unchallenged going forward if we don't havegood evidence. So the economic cost of committing to a therapy I think weighs very heavily on patients and families.


Mark, just maybe a quick aside. As we think about the global challenges, how important is new therapies that don't require a cold chain in theconsiderations for global access?


I think that's an excellent question. I think often we focus on developed markets and I see the enormous potential for this or other therapies thatdon't require a cold chain really to have some of the most significant impact. I've encouraged everyone that I've talked to to not just presume thatyou are going to see these therapies first in the US and in Western Europe, but that we should be thinking about them opening up globally.

I think of a story coming out of Peru where there was a nurse visiting. They had no clotting factor concentrate and they simply wanted to usesomething as basic as ice to control pain and swelling in a child's joint. The hospital had no refrigeration even to offer ice as a palliative therapy,let alone a medical intervention.

So to have a therapy that would be room temperature stable, that could be deployed in any healthcare setting would be truly revolutionary andopen up the world to access.


It looks like ALN-AT3 is room temperature stable out to multi-years, so that's a helpful feature.

Maggie, a question for you here. Treatment landscape in five years, what's your vision for that? How do you --? And maybe you can comment alittle bit in that answer on how you see gene therapy playing a role.


Absolutely. I think Mark did make a good point. It may be 10 years for gene therapy to really see a product that is safe and appropriate and easilygiven. Quite frankly, it just takes one of the many approaches to work. So is that in five years? Is that in 10 years? I don't know.

I think it is in the 5- to 10-year frame. Actually, I would even argue gene therapy is certainly one approach. In young people who have not hadchildren yet the worry always is there for mutations in the reproducing cells and all those issues, so that really -- I still think that it is quite reasonableto think why not have an oral agent. Let's take an oral pill once a day or once a month or, I don't know, subcu dose once a month.

But certainly I think many of the novel therapies that we see right here in Phase 1/2 trials are going to be out there. I think there will be even newertechnologies and more exciting approaches.

This is a very, very innovative, exciting era we live in. This is happening in many fields, not just the hemostasis thrombosis area. So I think we learnfrom each other. I think go look what they are doing in cancers, go look what they are doing in neurologic disorders.

I really think there are a lot of new novel therapeutics are coming along and we just need to see the safety and efficacy and reasonable cost andsimplicity for the patient. And, of course, patient acceptability and also have our global hat on. I think that's going to continue for the next fiveyears, the next 50 years. I think that is really important.

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Great. Thanks, Maggie. Maggie, maybe one last question here that we have is on the long-acting factors, they have recently been introduced; thereis some new ones emerging as well. Obviously you pointed out the comments around the factor IX products maybe having a bigger change ordifference.

But how do you see them playing out? Do you see them replacing existing recombinant factors over time? What is your sense of how that will playout?


Sure, sure. Well, you know I probably -- I participated in all the clinical trials of that -- of the Fc fusion proteins, just because they were the first onesout. And I have many patients who know what's going on and we got them on those studies. I love to do clinical trials.

So I have not only clinical trial experience, but now I have several dozen patients who have elected to go on these new products, and that bringsup the first point. The patient and the physician need to have an informed discussion. It is not my decision what a patient wants to do. I bring asmuch data to the conversation and make sure they understand how these agents work, what the differences are, what the requirements are. Wewant to see how they are doing, follow peak and trough levels, and assure that they are having a good response.

There is no question in my mind for the new moms with new babies a once-a-week treatment that does not require a port or a major IV, given inthe clinic by a well-recognized nurse, is extraordinarily life changing for these families. These kids do not have bleeds with once-a-week treatment.They slowly escalate. It just totally revolutionizes the disease for these young kids.

How will these drugs play out? I have to be very honest; if you're taking a drug that's twice a week, it's still invasive. Yes, twice a week is probablybetter than three times a week. Can you get by with a lower dose given the same frequency or a higher dose more frequently given? And what'sthe best way to do these drugs? We do not know.

We are really in a sort of a learning phase with these drugs. Will inhibitors be less frequent with these drugs? We really believe they will. We havean NIH grant. We hope that we will be funded to look with that, but these questions remain.

So if you can show that these drugs are -- that the impact will reduce joint disease, will reduce frequency of treatment, will improve quality of life,will be simpler for patients, will even reduce inhibitors, I think you've got a winner. It's not the winner, it's a winner.

That is the other thing; I think there are a large number of drugs that are going to be coming down the pike in the pipeline for new prohemostaticagents and I really think that there's going to be choice. I think that they are going to be comparing each other. I think there's going to be a lot ofthat.

But I think anything that improves the outcome of patients, their quality of life, their ability to participate in sports, their ability to just do everydaykinds of things -- work in a job that doesn't have to be sedentary. All those sorts of things really play into what is the best drug and will theseextended half-life drugs be the answer? I don't think they are the final answer. I think they are definitely an improvement; that's what I have seen.

There are no prospective trials to show that my perception is correct, so we have to wait for those. And again, [we use] the hemophilia populationto do these trials, so we do know if they are truly life-changing and produce the improvements we see in the clinical trials.


That's very helpful, Maggie. Listen, I think we should now transition to Benny's presentation. Benny, why don't you go ahead? I guess we will starton slide 42.

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P R E S E N T A T I O N

Benny Sorensen - Alnylam Pharmaceuticals Inc. - Senior Director, Clinical Development

Thank you very much, John, and good morning, everybody. Slide 42, if we take a look at a clotting system in a normal individual, it is composed ofpro and anti anticoagulants that in a highly-orchestrated way generate a timely and sufficient amount of thrombin to control against bleeds.

Now, in hemophilia, there is a deficiency of two essential pro-coagulants, the factor IX or the factor VIII, and ultimate result of that is that there isa profound defect of thrombin generation. What we are doing with ALN-AT3 is pursuing a therapeutic hypothesis that reduction of antithrombincan rebalance and restore normal thrombin generation.

Antithrombin, as previously mentioned by John, is a genetically-defined target. We know that antithrombin is one of the key natural anticoagulants.It inhibits factor VIIa, factor Xa and thrombin, and we know that low levels of antithrombin increases thrombin generation.

And, furthermore, in patients with hemophilia, low levels of antithrombin is a genetically validated target in the way that there are characteristicreports of patients with hemophilia having core inheritance of antithrombin deficiency. These patients, they experience milder bleeding, reducefactor requirements, and have fewer complications. And maybe most importantly, these patients are diagnosed much, much, much later in lifethan what is the usual for hemophilia patients without this rebalanced antithrombin low levels.

If we go to slide 43, ALN-AT3 has really undergone a very, very extensive preclinical evaluation. And what we have seen in our nonhuman primatestudies preclinically is that we can achieve a very potent antithrombin knock down and that potent antithrombin knockdown it is dose dependent,it is titratable, and it's durable.

Furthermore, we have developed the very advanced model of hemophilia where nonhuman primates have -- are being made inhibitor hemophiliaA for a short time. And in those animals, when we reduce antithrombin with ALN-AT3 up to an 80% knockdown, we normalize thrombin generation.And from the generation really -- as you can see on the next slide, thrombin generation is a very important biomarker for both the deficiency thatwe see in hemophilia, but also it is a biomarker that can help differentiate between severe, moderate, and mild phenotypes of the disease.

And as you can see in this little built-in here you can see the distinct difference between normal and severe. This is a very important marker for theeffect of ALN-AT3.

Based on that I will give you an overview of our Phase 1 study. This is a dose escalation study now in three parts, part A, part B, and part C. Theprimary objective is, of course, safety and tolerability and the secondary objectives, as well as exploratory objectives, is to look at antithrombinknockdown, thrombin generation as well as bleed frequency.

We have already completed and reported on part A, which was a single ascending dose study in healthy volunteers that were administered 30micrograms per kilogram ALN-AT3. Those data were reported earlier in January 2015, so we will today focus on part B. Part B is a multiple ascendingdose study in patients with hemophilia A or B, and here we have completed a total of four cohorts in three different dose levels.

Cohort 1 was dosed with 15 micrograms per kilogram weekly for three weeks and Cohorts 2 and 3 was dosed 45 micrograms per kilogram weeklyfor three weeks. Whereas Cohort 4 was dosed 75 micrograms per kilogram weekly for three weeks.

We have transitioned -- completed part B and transitioned to part C, which is also multiple ascending dose study. Now we are using a monthlydosing regimen and this is the dosing regimen we intend to carry forward in our Phase 3 trials.

Let's have a look at the demographics and baseline characteristics. What you can see in the first four cohorts that the mean age was ranging from27, 39, 42 years. A wide range; we have patients being 19 to 61 years old enrolled in the clinical trial.

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We have both patients with severe hemophilia A and severe hemophilia B enrolled in the study. And what you can see in the fourth row here isthe self-reported historical annualized bleed rate, which really indicates that the patients that have been enrolled in this study all have a moderateto severe bleeding phenotype with multiple bleed events -- on average, multiple bleed events per year.

Safety and tolerability first. We have not observed any serious adverse events and there has been no discontinuations in our study. There has beenno thromboembolic events and there has been no clinically significant D-dimer increases. Also the physical exams, vital signs, ECGs have all beennormal and we have not seen any clinical significant changes in any of our safety laboratory parameters being liver function tests, hematology,coagulation.

There has been 17 single non-bleed adverse events observed. The majority of adverse events have been bleed events, and these bleed events haveall been successfully managed with replacement factor administration and there has been no adverse events associated with factor administration.

But let's have a little bit more of a detailed look at these 17 single non-bleed adverse events: all mild/moderate, all transient. And what you can seehere is a complete list of these adverse events in the four cohorts.

Overall, you will see that these adverse events here really reflects either hemophilia or daily life. There has been one episode of injection site painthat lasted for two minutes. It resolved spontaneously and it was not associated with any other symptoms. There has been one episode of headachethat was temporally associated with administration of drug.

Let's look at 48. Here you can see the antithrombin knockdown of the multiple dose of ALN-AT3 in hemophilia patients. In Cohort 1, 15 microgramsper kilogram, you can see that we achieved a mean max antithrombin knockdown of 29 percentage. One subject had a maximum antithrombinknockdown up to 53%.

In Cohorts 2, 3, and 4 you can see that the mean max antithrombin knockdown was 54%, 59%, with subjects achieving up to 86% knockdown ofantithrombin. One important thing to emphasize here is evidently the duration of effect. And you can see that following the three weekly doseswe see almost a new steady-state level of antithrombin that maintains for several weeks, actual more than two months, which of course was veryencouraging and which established also the rationale for changing the dosing regime for weekly to monthly.

Let's look at slide 49. We've now seen that we can reduce antithrombin. Next part of the therapeutic hypothesis is to investigate if an antithrombinknockdown corrects thrombin generation. So what we have done here is a post hoc analysis where we have separated our data of antithrombinknockdowns into tertiles.

On the far left you can see the peak thrombin generation measurements in healthy volunteers in part A and then you can see the various peakthrombin generation values that we see at an antithrombin knockdown less than 33%, 33% to 66%, and more than 66% knockdown on antithrombin.What you can see is an antithrombin knockdown-dependent correction of thrombin generation to levels where, at antithrombin knockdown morethan 66%, we achieved thrombin generation that's comparable to that seen in healthy volunteers.

That corresponds to a more than 350% increase in thrombin generation in hemophiliacs.

We have further explored the pharmacodynamic effect of antithrombin reduction by looking at whole blood clot formation using ROTEMthromboelastometry. This is a technology that evaluates the physical changes of blood following a physiological coagulation stimulus. And whatyou can see here is the thromboelastometry profile of a normal individual on the left and on the right the thromboelastometry profile of a patientwith hemophilia characterized really by a very, very long clot formation time. So a very slow propagation of whole blood clot formation.

On slide 51, you can see the results of all the three patients that have had ROTEM analysis performed. What you can see here, just from looking atthe patterns, you can see that all these three patients experienced a very, very distinct and clear improvement in their whole blood clot formationprofile. And you can see that that improvement in the whole blood clot formation correlates to antithrombin knockdown.

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If we look in totality, the transformation time on day one was approximately 1,200 seconds and on day 35 the mean clot formation time was reducedto 320, corresponding an almost threefold improvement in whole blood clot formation. So looking at the antithrombin knockdown, the increasein thrombin generation, the improvement of whole blood clot formation, we performed an exploratory analysis of bleed events. What you can seehere is in the table below you can see the number of patients that have spent time at an antithrombin knockdown less than 33%, number of patientswith an antithrombin knockdown between 33% and 66%, and patients with an antithrombin knockdown above 66%.

In total, 12 patients spend 509 days at antithrombin knockdown less than 33%, and during that period there was a total of 33 bleed events thatcan be extrapolated to an annualized bleed rate of 22 bleed events per year. Nine patients spent a total of 414 days at an antithrombin knockdownbetween 33% and 66%, and there they experienced only 18 bleed events corresponding to an ABR of 14. And two patients have spent a total of106 days at an antithrombin knockdown more than 66%. And none of these patients experienced any bleed events.

To kind of put this into perspective, on slide 53 we have emphasized a case from our study, patient 400-02, and this really illustrates the wholeconcept of ALN-AT3 in hemophilia. Let me walk you through this.

What you see in this illustration here is point one; let's have a look at the antithrombin percentage knockdown in blue. So following injection ofALN-AT3 on days zero, 7, and 14, you can see that the patient experienced a distinct reduction here in his antithrombin knockdown, down to an86% reduction in his antithrombin.

As his antithrombin goes down in purple, you can see that the peak thrombin generation goes up. It goes up to levels at the median of approximatelyaround 100 to 115 nanomolar peak thrombin, which is comparable to the average peak thrombin that you see in healthy male volunteers. Whatyou can see as well is, as his antithrombin starts to recover out on day 120 approximately, you can see that his thrombin generation then goesdown.

Meanwhile, if we look at his bleed events and factor administration, during the knockdown period of antithrombin where he still had no clearcorrection of his thrombin generation, he experienced two bleed events that was managed with factor administration. However, during the periodwhere he had a substantial knockdown of antithrombin and correction normalization of thrombin generation, you see that this subject experienceda 114-days bleed-free period. When his antithrombin recovers and thrombin generation goes down, unfortunately this subject started experiencingbleed events again.

During the entirety of observation here we also look at D-dimer. As you can see here, D-dimer as a measure of saturated or pathological clotformation remained completely unchanged.

On the far right, just to put this increase in thrombin generation into perspective, we have done a titration with factor VIII in this patient's plasma.And what you can see is that if we look at peak thrombin generation ranging from 100 to 115 nanomolar, that is achieved when your factor VIIIlevels are above 25%. So the reduction of antithrombin and correction of thrombin generation achieved with ALN-AT3 is kind of comparable tomaintaining a constant trough level of factor VIII way above 25%, so comparable to having mild hemophilia or being comparable to not havinghemophilia at all.

Overall, if we look at the ALN-AT3 product opportunity based on the preclinical and now extensive Phase 1 clinical data that we have, we believethat there is a significant potential for a new therapeutic approach here in hemophilia as well as rare bleeding disorders. And we believe this is ahighly differentiated approach, where subcutaneous administered drug once a month really could be playing a central role in changing diseasemanagement by rebalancing hemostatic capacity.

Also, reduction of antithrombin has nothing to do with administering factor VIII and IX. So there is the vision of potentially eliminating inhibitorformation by not exposing or minimizing exposure with factor VIII or IX. We believe that this technology will work equally well in both patientswith hemophilia A and hemophilia B, hemophilia A patients with inhibitors and hemophilia B patients with inhibitors.

And I think it's worth mentioning that in particularly patients with hemophilia B and inhibitors really are left with very, very little new promise, andmaybe this is the only opportunity these patients really are left with.

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We also believe that the product opportunity here and the value is supported by pharmacoeconomics. There's some very, very strong, well-organizedpatient advocacies; not just in developed areas, but also in developing areas, as I'm sure Mark could speak to more. And there is a really significantopportunity for a global expansion as this is really a product that can come to the patient and the patient does not need to come to the product.

If we look at the current market needs here in patients with pedophilia A and B without inhibitors, the key need here is really to make sure thatinhibitor development is minimized to make sure that the drug can be administered by very, very simple means without very advanced, complexmixing devices. Also to try to aim to get away from the need of an invasive route of administration. IV is really extremely burdensome. And I -- Ihave really never spoken to any hemophilia patient in my life that has not been explaining concerns about the need to constantly poke the vein.

Finally, long duration, real long duration. If we can get to a once-a-month treatment regime, I'm sure that that will be a very, very important need.

Finally, the inhibitors. I just want to say here there is a massive burden of treatment; there is high cost and the bypassing agents that are availablereally have significant shortcomings. So look at the potential target that we have of segments here.

You can see that the biggest segment is evidently patients with severe hemophilia A and B without inhibitors. The smaller segment, however highunmet need, are patients with inhibitors. But we also believe that ALN-AT3 can address other rare severe bleeding disorders and maybe evenpatients with type III, Von Willebrand disease.

If we look at the clinical development plan, the data that we have generated so far is really very encouraging and has put us on a path where webelieve we don't need a separate Phase 2. So we are currently targeting to make a progress from our current Phase 1 study into a series of Phase1 trials targeting patients that are currently receiving on-demand therapy, non-inhibitor patients as well as inhibitor patients, as well as a Phase 3open-label extension study and safety study that can enroll both non-inhibitor and inhibitor patients.

Later on we will conduct pediatric studies as well as explore the opportunity in rare bleeding disorders.

So in summary here, ALN-AT3, we believe, represents a novel investigational approach for potential treatment of hemophilia and rare bleedingdisorders and doing so by rebalancing hemostasis to normalize thrombin generation.

Ongoing Phase 1 study in both healthy volunteers and hemophiliacs have shown that ALN-AT3 has been generally well tolerated. We've seen noserious adverse events. All the AEs have been mild/moderate and transient. No discontinuations and no signs of pathological clot formation.

There is now also initial evidence of clinical activity and rebalancing of hemostasis in severe hemophilia. We've seen up to an 86% antithrombinknockdown with a mean maximum AT knockdown of 59% in the 75 micrograms per kilogram. The effect has been durable and, thus, supportiveof a once-monthly subcutaneous dosing regime.

And we've seen up to a 300%, 350% increase in thrombin generation, which really represents normalization of thrombin generation in severehemophilia. That has been supported as well by marked improvement in whole blood clot formation and the exploratory post hoc analysis of bleedevents indicates that if we achieved a high antithrombin knockdown, we may be able to achieve zero bleed events for patients.

Likewise, on slide 59, just to give you a little bit of a prospect of the next steps, we plan to advance to pivotal trials in mid-2016. The additionalPhase 1 clinical results reporting on monthly dosing regimes will be presented late 2015, and we also are on track to start our open-label extensionstudy in 2015.

We believe that hemophilia and rare bleeding disorders represent a very attractive commercial opportunity as well, and there is really a -- theclinical development plan is really so that it is trying to maximize this product opportunity. And I think, John, maybe you will take the upcomingALN-AT3 events?

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Sure, Benny. Slide 60, just to highlight again, pending abstract acceptance, we are hoping to present data probably from around 20 severe hemophiliasubjects at ASH in December.

And then as Benny mentioned, in addition to that presentation, we will be initiating our Phase 1 open-label study later this year, giving patientsthat have been in the Phase 1 study the opportunity to get extended dosing. And we'll probably report data from that Phase 1 only study at leastonce per year. Then we also aim to open up our Phase 3 study in middle of 2016.

So let's pause there. We do have some questions, Benny, that have come in. Two that I think can be linked I will ask first, which is, in the Phase 3trial, what would be the primary endpoint and how long will it take to complete the Phase 3? So do you want to answer that?


So, firstly, the primary endpoints. We're really fortunate here by multiple years of clinical development in hemophilia, so there is a very clearregulatory path. The primary endpoint in a Phase 3 trial exploring a new treatment of hemophilia is the annualized bleed rate, so that is going toalso be our primary endpoint, the annualized bleed rate.

The completion of a Phase 3 trial is, of course, highly dependent on recruitment. However, based on the interactions we had at the ISEH, the interestthat we are experiencing from external and key opinion leaders and investigators is really high, so I feel very confident that we can enroll even abig Phase 3 trial in decent time.

I'm not going to promise exactly how long it is, but as a minimum a Phase 3 trial needs to look at the analyzed feed rate for six months. There'sprecedent for that in the regulatory kind of -- in regulatory agencies.


Maybe we can ask Maggie. Maggie, how long did the Eloctate or Aprolix studies take to complete for Biogen?


You know, absolutely it depends on enrollment, which depends also on the number of sites. And so for those studies, very interestingly, they wereall international and I'm sure that's going to be true for AT3. Even so, it takes two to three years at minimum to complete these studies. I think itreally is a time commitment. It does take a while and we did have the extension study, so I think you're right on with what we would expect.


Yes, terrific. Good.

Another question that came in, which was related to the analyses that were done, the post hoc analyses that were done in the study using a tertile.The question is: is the tertile something that was done arbitrarily or where there other data that supported the use of that type of post hoc analysis?Benny, do you want to comment on that?


Yes. So they are certainly not done random. We have very, very extensive animal data points to that separating the antithrombin knockdown intertiles actually will give us a very, very clear understanding of the therapeutic hypothesis.

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If you, for instance, look at the nonhuman primate data, you can see that within an 80% knockdown, actually from the change to 60% to 80%knockdown, which is just that tertile, is really where we see the marked improvement in thrombin generation. So it was important for us to kindof validate what we have seen preclinical, clinically, and I think important really for the whole therapeutic hypothesis to show this link betweenantithrombin knockdown correlated to increase in thrombin generation. And both correlate to a very, very clear improvement in the risk of bleedingand bleed events.


Thanks, Benny. Another question that has come in here is there seems to be a lot of variation in thrombin generation. Can you comment on that?


So thrombin generation assay is a global hemostatic assay which is highly sensitive, and with that sensitivity comes quite a bit of variation. So thatis -- it's really down to the assay there is a lot of variation. That variation arises both from pre-analytical variables, such as how to take the bloodsample, how to store the blood sample, spin it, send it, and also then the actual kind of preparing the sample is fairly complex. There's a lot of also-- there's a lot of pre-analytical variation.

Then there's a bit of analytical variation as well. All together that will cause quite a bit of fluctuation.

Now we, of course, also look at the data very frequently, so we put a lot of pressure on these pre-analytical variables. We have done some justexploratory assessments of what would happen if we just took a whole bulk of samples and ran just on one plate in this thrombinoscope machine,and doing so we can eliminate a lot of that variation group.

And so some of the fluctuation we see is really due to we put a lot of stress on those pre-analytical variables. We could probably eliminate those,but then we won't have the data to look at, which is important for both internal and external progress of this trial. For the investigators it's veryimportant to have a look at these data to keep the momentum of the trial ongoing.


Good. One question that just came in, Benny, which I can rephrase a little bit from what was written by the audience is really about VWF disease,von Willebrand disease, saying there's not much discussion on this disease area today, but is it an opportunity that we are considering at Alnylam?You want to comment on that?


Sure. There was really -- a few months back my colleague, (inaudible), and I we found a very, very interesting presentation from a German groupthat had looked into two patients, two siblings with severe von Willebrand disease, type III. One of these patients, she bled very frequent andrequired prophylactic administration of von Willebrand factor concentrate, whereas the other one really didn't bleed much frequent and didn'trequire prophylaxis.

It appears that the patient with the mild bleeding phenotype had an antithrombin deficiency, so that is of course a very, very strong geneticvalidation of potentially approaching von Willebrand disease type III.

Now, first things first here, the opportunity in von Willebrand -- in hemophilia is very, very high and as we can see here from both Maggie and Mark,there's a massive gap. There's a need for us to really accelerate and make progress here. That doesn't mean we won't be interested in von Willebranddisease type III or other rare bleeding related disorders. We will continue to be interested in that and we will continue to pursue those opportunities.

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One other question that just came in as well, Benny, is do the adverse events listed on our slide, do they belong to a larger family of events thatmight implicate an allergic reaction to drug administration?


No, no. No, not at all.


Good. Let's see, one other question here maybe. We have maybe time for one left is thinking about our therapy in reference to ACE910, which is avery promising approach that has come out of Roche and shoe guy, do you want to comment on ACE910?


I agree that the biospecific antibody concept is interesting and I think the data are very exciting as well. Now our approach is a bit different. Pointone, we are administering a very, very small volume. We can administer this once a month.

This is not a protein; we're not a protein so we will not be immunogenic to the same degree as a biospecific antibody. So we do not expect to seeanti-drug antibodies emerging. An anti-drug antibody will potentially be neutralizing and could thereby could prohibit further kind of advantageof such an administration.

I think what is very important here is no one should be left out, and the patients with severe hemophilia B, they have no benefit of a biospecificantibody that is supposed to mimic factor VIII. In particularly, maybe the patients with severe hemophilia B and inhibitors right now, ALN-AT3 isreally their only hope and promise I think for something groundbreakingly new that can happen.

So I see us as being a very strongly differentiated from ACE910. But you know as a clinician as being also a big supporter of the hemophilia community,I welcome these data as well. I think they are exciting.


They are exciting. One maybe last, last question that just came in. Question is the 225 microgram per kilogram dose monthly that we are currentlydoing within the study, part C, is that dose going to be the dose that is the final dose and do you --? Question for -- would that be what you believewill be the final dose at ASH?


We will continue dose escalating in part C and this is important because we need to fully kind of explore and investigate the full therapeutic index.And we believe that there are really no lower thresholds of antithrombin for patients with hemophilia.

So, no, I cannot guarantee you that 225 is the final dose. I can guarantee you that we will continue dose escalating because we want to establisha very strong safety margin, understanding of the whole concept of antithrombin reduction in hemophilia as a way to rebalance hemostasis andnormalize thrombin generation.

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And obviously, all those data will be presented at ASH. I'm sure people will be -- we hope; we don't know all the data yet, but we certainly hopethe data will come together nicely for continued presentation of this therapeutic approach.

So I think with that I am going to hand it over to Josh for some final comments and then I think we're out of time.


Great. Thanks, everyone. This concludes our RNAi roundtable for today. The replay, slides, and the transcript of this event will be posted on theCapella section of the Alnylam website later today, so you can view those. And we look forward to your participation tomorrow as we discuss ourALN-CC5 program in development for the treatment of complement-mediated diseases and in the weeks that follow on the topics that are shownhere on slide 62.

That concludes the event. Thank you, everyone, and have a great day.


Have a great day, everybody. Bye-bye.

Operator

Ladies and gentlemen, this does conclude today's program and you may all disconnect. Everyone, have a great day.

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