Gene Therapy

HFA: Together We Rock!

admin May 6, 2018

Laurie Kelley and Chris Seistrup — Laurie Kelley with Chris Seistrup, a cyclist who will raise money for Save One Life

The Hemophilia Federation of America sure knows how to throw a party! And a three-day meeting, all aimed at educating the community about bleeding disorders while providing a busy but intimate venue for meeting up with old friends, acquaintances and business colleagues. And held in Cleveland, with a final evening a celebration at the Rock and Roll Hall of Fame, the theme “Together, We Rock” was absolutely true and we did!

I was able to attend some sessions while there, in between visiting our Save One Life booth and greeting sponsors, donors and interested people, and chilling with some very great friends (Debbi Adamkin, Neil Herson, Ray Dattoli, Melissa Compton, to name only a few). First was an invitation-only meeting with Genentech about mlibra, and specifically the recently reported deaths. About 20 consumers, all key opinion leaders associated with hemophilia organizations) attended. I won’t go into that here in much detail, as the meeting completely corroborated with the article Paul Clement wrote in the May issue of PEN, available on our website.

Laurie Kelley and Liliana Gomez, with her award for her work in Puerto Rico

In a nutshell, though, Genentech shared how Hemlibra has been granted Breakthrough Designation Status by the US FDA to fast-track approval of Hemlibra for noninhibitor patients, based on the HAVEN 3 study data. Conversation turned to the five deaths, out of the 600 current users of Hemlibra globally. Genentech walked us through each death, one by one, what was known and what was reported. We now know that two were Americans, one of whom was in a clinical study. While the explanations all made sense, Ray Datolli, a COTT representative, remarked, “It’s always a clinical study, and it’s always 1981.” The other attendees also commented that the delay in learning of the five deaths was a problem; the community wants to know sooner about these “adverse events.” Genentech then reviewed why they cannot comment on the deaths, for reasons we spell out clearly in our article, and in some cases, the families of the deceased themselves did not want the information released.

Debbi Adamkin, executive director of the Florida Hemophilia Association commented too that the community needs to be educated that Hemlibra is not a cure, and many think it is!

Laurie Kelley with Crystal Higgins and Tracy Farmer

To learn more about Hemlibra, please read our article in the May issue of PEN.

Another good session was on inhibitors, by Vanessa Byams of the CDC. We learned that the CDC hosted a second national inhibitor summit in January 2017 and is closely following inhibitor trends in our community. Its goal is to share information from the community, and to discuss how to collect high quality data, to make sure inhibitor tests are accurate. NHF’s MASAC has an Inhibitor Prevention and Eradication Working Group, which has led to a national collaborative effort to increase enrollment of babies with hemophilia and inhibitors in the CDC Surveillance study. The bottom line is, all hemophilia patients are at risk of inhibitors (with certain exceptions) and there is a lot of research happening on inhibitors. Vanessa said that in the last 18 months alone there is “an incredible movement and action” regarding inhibitor research. “The road to inhibitor prevention starts with national surveillance, including regular screening and early detection If you detect it early, the better the chance of eradicating it.”

One clear hole in our weekend was Barry Haarde: we were all missing his presence, as HFA was truly a home away from home for him. His sister Emily came to fill in for him, and we all shared Barry stories, while admiring his contributions to HFA and Save One Life, which helped so many around the world. With sadness and sweetness, we all felt his absence all too well.

On Saturday morning, Novo Nordisk sponsored a “B Yourself” symposium for families with hemophilia B. It was very lively, as the audience could participate in answers using the buttons at their desks; answers were tallied and displayed instantly on the screens, from tables designated with rock and roll names: The Rolling Stones, the Beatles, Prince, etc. It made it all the more fun. The topic was mostly about pharmacokinetic (PK) testing, with different patients sharing about their different half-lives, and different dosing schedules. It got pretty technical but was fascinating. It really is imperative that every person with hemophilia know their PK levels, because we now know that you cannot dose just by weight and correction percentage—you do need to know your half-life. We will have some great articles about that in the November issue of PEN.

Laurie Kelley and Pat DeRatto, long time
friends and hemo-moms!

I spoke with dozens of people, all involved in the community, from patients, to advocates, to chapter leaders to industry reps. Two main themes really became clear, one scary and the other exciting.

Scary? Funding in the community is being restricted. Every executive director of a chapter I spoke to commented on this. Our pharmaceutical sponsors are pulling back funding, perhaps as the marketplace is glutted with products, and we expect some consolidations and acquisitions (like Sanofi buying Bioverativ, and Takeda making moves on Shire?). No one is sure what will happen, but some programs may need to be cut.

Exciting? Gene therapy. More than one person said to me, “It’s not a matter of if anymore, but when.” Gene therapy is coming. How will it impact our lives, both as patients and as community employees?

We don’t know yet, but as we rocked the night away Saturday night to a great band at the Rock and Roll Hall of Fame, we celebrated the great advocacy and grassroots work of HFA and its team, celebrated being a family of people with bleeding disorders, and excited about what the future holds.

On the Horizon: HFA Part 1

Laurie Kelley April 30, 2018

Last week the bleeding disorders community met in Cleveland, Ohio at Hemophilia Federation of America‘s annual meeting. It was a fabulous time to meet with friends and colleagues, and to learn about new treatments in inhibitors, new drugs in the pipeline and about psychosocial issues. One of the best attended sessions was the one on gene therapy. Entitled “On the Horizon,” the session was a 90-minute review of new products coming our way, and an overview of gene therapy, how it works and who is working on it.

Dr. Sanjay Ahuja, medical director of Rainbow Children’s Hospital, first spoke about “New and Emerging Therapies.” Expression Therapeutics is working on “ET3i,” a recombinant
factor VIII (rFVIII), that should give a higher yield, with the focus on lower cost per unit.

Another interesting therapy is called “transgenic.” Pharming Group has found a way to derive transgenic rFVIII from the milk of rabbits. Ahuja explained that scientists have learned how to take a human gene that makes factor VIII, put in rabbits, and have factor expressed through their milk. This is called “lacto-recombinant factor.”

This generated laughs from the audience, and one man gestured like he was milking a cow. And while Ahuja joked that we could get our kids to drink more milk finally, the actual drug would not be in milk to drink, but commercially available as an infusion. It would be cheaper to produce, with a high yield, making factor much more affordable.

“New things and better things coming,” Ahuja said.

Many people in the audience already knew about the innovative therapy called emicizumab (commercial name: Hemlibra), a bispecific monoclonal antibody that mimics factor VIII by bringing together activated FIX and FX together, replacing the function of FVIIIa. It’s not a factor product! There was a brief discussion about the deaths associated with its use [see our upcoming article in PEN for a detailed discussion on these]. Bioverativ and Shire are also working on bispecific monoclonal antibody and Shire’s is actually a bi/trispecific. These drugs are called “FVIII-Mimetic.”

Another innovation for FIX is from Salk Institute/Arcturus Therapeutics, currently in pre-clinical studies. It’s not gene therapy, though it involves taking RNA to the liver to
make factor.

On the horizon for inhibitors are products in the FVII market. HEMA Biologics/LFB, are working on an activated FVII. rEVO Biologics/LFB are working on FVIIa in transgenic rabbits.

Even a long acting, subcutaneous FVIIa is being made by Catalyst Biosciences and OPKP Health.

Perhaps the biggest surprise of all is rFVIII being made in lettuce at the University of Pennsylvania, and this you do eat!

Dr. Stacey Croteau, medical director Boston Children’s Hospital, and Associate Director of the Boston Hemophilia Center next spoke about gene therapy. She gave a brilliant overview, too detailed for here, but if you look at the slides, you’ll get a sense of just how much activity is underway. And all through the four-day conference, I kept hearing chapter leaders talking about not “if” gene therapy occurs, but “when.” More and more, it is becoming a reality.

Dr. Croteau first explained that there are three basic types of gene therapy:

1) Direct therapy (injection into the patient)

2) Cell based (in which you take cells out, alter the genes, then reintroduce the altered cells to the individual, called ex vivo)

3) gene editing (going directly into a defective gene to make it work)

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There was a good discussion of how adeno-associated viruses (AAV) are mostly used as the vehicles (vectors) to introduce the altered genes into the patient. Why a virus? They are good at replicating—viruses need to quickly replicate to infect the host and survive. But Dr. Croteau stressed that the AAV8 is stripped down and rendered harmless, so just the FIX gene is left. It’s then introduced back into the patient and goes to the liver (AAV vectors love the liver!), embeds into hepatocytes (liver cells), degrades and becomes part of that cell and starts to express normal coagulation factors into the bloodstream.

Dr. Croteau explained how difficult gene therapy is. You must get the gene delivered to the right cell type in sufficient quantities; then it must switch the gene on, all the time avoiding body’s natural immune response.

In 2011 there was the first successful AAV gene therapy for hemophilia B. With high doses, the patients in the clinical study had their factor levels go from severe to moderate and even to the mild range.

Not all gene therapy research is using AAV; there are all types of AAV vector subtypes. Looking at the slides, why so many? Not everyone will be eligible to use a particular vector. Just like with factor, one gene therapy won’t fit all. Dr. Croteau concluded that it’s good we have several options for gene therapy, and many look very promising!

To learn more about gene therapy trials, you can look at Clinicaltrials.gov

And very honorably, the speakers reminded us that those patients who have volunteered and are volunteering for new therapies and gene therapy make it possible for the rest of us to enjoy a higher quality of life. Indeed, they are our heroes.

This was a great session to attend; thanks to Drs. Ahuja and Croteau for their presentations! Please read HemaBlog next Sunday when I’ll give an overview of the entire HFA meeting… which was fantastic!

It’s New! Therapeutic! And Coming Soon!

Laurie Kelley September 3, 2017

With a record-breaking 2,987 in attendance, NHF’s 69th annual meeting in Chicago on August 24-26, was the largest and most varied!

Two of my favorite speakers at NHF Annual Meetings and whose sessions I always seek out, are Glenn Pierce, MD, PhD and Steven Pipe, MD. And they did not disappoint! Although it would take an entire blog to list all of the accomplishments of these two highly respected individuals, suffice to say that they are both very knowledgeable about bleeding disorders in general and about clotting factors, novel treatments and gene therapy in particular. And they both share a relatively rare ability: they are able to explain complex medical topics to consumers in terms that we can understand (okay, mostly understand!)

In Dr. Pipe’s Friday morning session, “The Cure Horizon: Point/Counterpoint”, whom he co-hosted with Dr. Rebecca Kruse-Jarres, Pipe played the part of advocate for gene therapy and his counterpart advocated for “small molecules” (novel, non-factor treatments for preventing bleeds). Later that day Dr. Pierce gave the plenary session on “New Treatments and Gene Therapy.” Although both sessions covered some of the same information, they did so from different perspectives and it was beneficial to attend both.

Here’s a recap of the two talks regarding new therapies on the horizon. On the “small molecule” side there are three different approaches being investigated that can reduce bleeds without the use of factor. One therapy, emicizumab, or better known in the community as ACE910, is likely to be the first to market—and soon. ACE910 is a therapy for hemophilia A ,with or without inhibitors. It is a bi-specific antibody (meaning the antibody can grab two different factors at once) designed to mimic the function of factor VIII by bringing together factors IXa and X to initiate clotting. It is
administered weekly as a subcutaneous injection. Genentech’s ACE910 has been granted priority review by the FDA and their license application may be approved as soon as February 2018. (It was also mentioned that repeated doses of aPCC, a by-passing agent sometimes used by people with inhibitors, in conjunction with ACE910 can result in unwanted clotting.)

A second approach involves blocking the function of a player in the clotting cascade called tissue factor pathway inhibitor (or TFPI) that serves to check the clotting process so it does not runaway out of control. This therapy, called concizumab or anti-TFPI, is also an antibody and also administered subcutaneously. It blocks the function of TFPI and is effective in reducing bleeds in people with hemophilia A, B as well as those with inhibitors. Anti-TFPI has entered phase 2 clinical trials this summer.

The third approach uses genetic material that blocks a cell’s ability to produce antithrombin, which like TFPI, serves as a check on
coagulation. Called fitusiran, this agent interferes with the cell’s RNA involved in the production of antithrombin—in short, it prevents the cell from making antithrombin and restores a “balance” between the two parts of the clotting process: one that makes clots and the other that stops the clotting process. This agent is in phase 2 clinical trials.

All three of these novel hemophilia treatments were referred to as “disruptive therapies.” This is similar to the term “disruptive technologies,” which “refers to any enhanced or completely new technology that replaces and disrupts an existing technology, rendering it obsolete. It is designed to succeed similar technology that is already in use”1. Examples of disruptive technologies include DVRs, which displaced VHS recorders; PCs, which displaced both typewriters and mainframe computers; and laptops, which displaced desktop PCs and might soon find themselves displaced by tablets; and tablets which may be replaced by ever-larger and more powerful smart phones, which themselves have disrupted the telecommunications industry. The emerging small molecule therapies for hemophilia will be more convenient, last longer, be easier to administer and will likely be less expensive than clotting factor concentrates. They will upend the market for factor concentrates, which have been the mainstay treatment for hemophilia in developed countries since the late 1970s. And, of course, gene therapy is on the horizon, which will then disrupt the market for small molecule therapies for hemophilia.

And what about gene therapy? Both speakers mentioned significant advances made by two companies, Spark and BioMarin, which have been successful in converting individuals with severe hemophilia into mild hemophilia, with Spark reporting sustained factor VIII levels of 12% and 14% in two patients. These levels are high enough to prevent spontaneous bleeds. This brings up the question: what level of factor expression represents a cure? Should we wait until gene therapy can cure hemophilia by raising factor levels above 50%? And of course, the question of cost is forefront in everyone’s mind. These questions have yet to be answered.

The times they are a changin’! Never before have we had so many factor products on the market, with new factor products, as well as disruptive small molecules and gene therapy, still in development. What is certain is that, in the near future, hemophilia therapy will look dramatically different than it does today.

1. https://www.techopedia.com/definition/14341/disruptive-technology

What Does Gene Therapy Mean to YOU?

Laurie Kelley July 9, 2017

Written by Laurie Kelley
Originally published in PEN, May 2017

Ladonna Pettus remembers the cover of Hemalog, a hemophilia magazine from 1990, promising “A Cure by the Year 2000?” It seemed at once like a vision and a done deal. Ladonna’s son with hemophilia was around two at the time. She recalls, “I had such hope. He is almost 30 now.”

Many parents who remember that magazine cover had those hopes. Their children are adults now, and although gene therapy trials are underway, it seems that the passion and dreams for a cure have been tempered. Alvin Luk, head of clinical research and operations at Spark Therapeutics, is working on hemophilia gene therapy. He offers, “We all underestimated the complexity of gene transfer.”

Maybe this is why, when I repeatedly asked 2,600-plus hemophilia “friends” on Facebook about their thoughts on gene therapy, only a handful of people replied. I’m sharing their comments here. Normally, the hemophilia community is vocal and active. Does this lack of response indicate that we are mostly unaware when it comes to gene therapy? Are we not sure what it is?

Defining gene therapy: A cure?

Parents and patients sometimes use the terms “gene therapy” and “cure” interchangeably. But the definitions aren’t the same. When we think of a cure, we think of eradicating the disorder or disease. In other words, a person with hemophilia no longer has it. In fact, a permanent cure for hemophilia already does exist. Steven Riedle notes that his brother with hemophilia had a liver transplant in October 2016, and is indeed cured of hemophilia. But a liver transplant is not a feasible option. 1 Many patients and caregivers are waiting—hoping—for a safe, widely available therapy that will cure hemophilia permanently. Yet we may need to adjust our definition of cure. Community members who responded to my questions seem to realize that most current gene therapy trials promise to make hemophilia less severe by increasing circulating levels of factor in the blood. Very few patients or parents understand gene therapy as thoroughly as Ray Stanhope, former National Hemophilia Foundation president, and person with hemophilia. He defines gene therapy as “the use of a viral vector to modify cells in the body to produce an additional specific protein which is either missing or produced at a lower than normal level in a person with hemophilia.”2 What Ray describes is not necessarily a cure, but an improved therapy.

What level of success?

If current gene therapy trials promise to increase circulating factor in the bloodstream, what level would be considered successful—a “cure”? Remember that severe hemophilia means less than 1% circulating factor, moderate means greater than 1% to 5%, and mild means 6% to 50%. Anything over 50% is considered in the normal range. 3 For Ray, levels of circulating factor would have to be well over 40% and closer to 50% (normal) to be considered a cure.

But others think that even converting someone from severe to mild hemophilia could be considered a success. Nichole Foley writes, “I think taking a person from severe to mild hemophilia is enough of an advantage for some of these kids that have constant challenges, and hopefully it will alleviate inhibitor issues.”

Bryce Loehrke says, “If gene therapy could permanently bring me to the levels of even mild hemophilia, I would consider myself cured for the most part. Having severe hemophilia A, I’ve often said that those with mild hemophilia don’t even have hemophilia. I don’t mean to diminish the fact that they still have issues from it periodically, but often with much less severity or frequency, sometimes to the point of not knowing they have it until later in life.” Tina Ruis takes this even further. “My 24-year-old son with severe hemophilia B—his left leg is unbearable. His calf is massive, and he can barely move without a walker. Levels of 11% to 15% would be worthwhile; over 25% would make me cry with joy.”

Stephen Brewer would be happy if gene therapy worked, even if it wasn’t permanent: “I would accept having mild hemophilia even if only for a few years.”

Chris Templin and his daughter both have hemophilia B. Chris notes that aiming for “mild” hemophilia is fraught with inconsistencies. “I think it’s interesting how people think all those with mild hemophilia bleed less then severe hemophilia patients. I know some milds who bleed more than some severe patients.”

The price of success

If gene therapy is successful and becomes available, how much would it cost? Some families think that because gene therapy trials are being held at university hospitals and hemophilia treatment centers, its cost may be lower than that of current commercial therapies. But this is not correct, because the trials are underwritten by pharmaceutical companies and the manufacturing process would ultimately need to be upscaled by a commercial pharmaceutical company.

The issue of cost for a new therapy is complex, and includes these questions:

• What is an acceptable therapeutic factor level: moderate, mild, normal?

• How long will the treatment last: three years? permanently?

• Will other factor products need to be used during the treatment period?

Ray estimates the cost of a one-time treatment of gene therapy at “close to $1 million, given the low number of patients, the cost of research and development, and assuming that the therapy is successful for four years.” He adds, “For the manufacturers, as much as they can charge; for the insurers, the least amount they have to pay.” Nichole Foley doesn’t care: “Cost-wise, I am sure it will be astronomical, but if [gene therapy] enables kids to live a normal life, I’d think it would be worth it!” Bryce believes, “If there’s an effective lifetime cure, $250,000 will be a lowball figure. We need to convince insurance providers of the long-term savings of a permanent or semipermanent cure.”

What if gene therapy is good for only a few years?

The term “cure” isn’t applicable at all if gene therapy—even if it brings your factor levels to normal—lasts for only a few years. This is a real concern.

Ray explains: “Given that the current vectors are viral and the immune system develops a response to that vector so that once used, it cannot be used again, this is problematic if the period of time that the treatment persists is short. There may not be time to develop an alternate type of vector. However, given the speed at which medical advances are occurring and accelerating, having the treatment persist for more than ten years might be enough to get you to the next vector, whatever that might be.”3

Amber Brandt, mother of a child with hemophilia, worries, “Regular factor is so expensive, I don’t see gene therapy being cheap by any means. And I’m sure it would be a huge struggle to get insurance to cover it. But if it only lasts a few years, I don’t even think it would be worth [trying] it at all.”

Wait-and-see approach

Patients who don’t see any solutions to these concerns may adopt a wait-and-see approach. Some are inherently mistrustful of playing with genes, or of the whole commercial industry of factor manufacturing. Some feel that current therapies are good enough for now.

Brandi Worthington admits, “I don’t know anything about gene therapy.” Amber adds, “It’s fascinating, but I would never choose that option for my son. He can choose that if he wants when he is an adult.” “I won’t be a first adopter for gene therapy by any means,” declares Bryce, “primarily due to distrust of the entire pharmaceutical industry for various legitimate and historical reasons. We need to know the consequences as well as benefits [of gene therapy].” Ray concludes, “Depending on the factor levels achieved and the duration of the treatment and the usable number of vectors…I might wait and see.”

Stepping-stone to a cure

Ray understands well the nuances and importance of educating the hemophilia community about gene therapy. Parents and patients will one day need to make an informed decision about whether to participate in it. “We as a community first need to define the parameters of what we would consider a cure,” says Ray. “I have always had a strict interpretation of this word. A cure would be a single treatment that provides normal hemostasis over the lifetime of the person living with hemophilia. Anything less than this should be considered a stepping-stone toward a cure.”

Stephen still has hope and carries the definition of cure even further. “Looking forward, a cure would include increasing circulating factor levels, [and] eliminate hemophilia from future generations [of a family].4 This is the ideal I hope for.”

1. Factors VIII and IX are produced primarily in the liver, although the cells lining the blood vessels also produce and hold reserves of factor VIII for release into the bloodstream when needed. Replacing the liver indeed cures hemophilia, but this is not deemed a viable option for treatment because it is too risky. Only patients with hemophilia who face liver failure are considered for this operation.

2. A vector is a modified virus used by molecular biologists to deliver genetic material into cells.

3. Among the general population, normal factor levels are between 50% and 150%, with most people being close to 100%.

4. Changing the genetics of future generations is not gene therapy, but human germline engineering. This practice is currently banned. It’s highly unpredictable, dangerous, and considered unethical.

Gene Therapy: Lookin’ Good!

Laurie Kelley April 30, 2012

I happily drove an hour to Westwood, Massachusetts to attend the New England Hemophilia Association’s Springfest, a gathering of local hemophilia families and the companies and medical people who serve them. It was a glorious, sunny day and a wonderful event.

Val Bias, CEO of NHF, attended to present an overview of NHF’s programs and also how funding is raised and where it is spent. Here are some stats:

• There are 57 full time and part time staff at NHF over 10 states

• There are 8 regions for HTCs now, down from 12

• NHF has a PDF you can download called “50 Steps to Cultivating Donors”

• 50% of the NHF’s board of directors are not related to hemophilia

• 52% of its budget comes from pharma

Val stressed to the audience to get involved locally, and to consider joining the NEHA board. He made a compelling plea and is an excellent speaker. Many people told me later they thought Val is a gifted presenter and a wonderful leader for our community.

Next up was a great presentation on gene therapy and new products coming soon by Dr. Ellis Neufeld of the Boston Hemophilia Center. Dr. Neufeld did an amazing job of taking highly complex material and breaking it down for us. Some highlights:

• The St. Jude gene therapy trial that has been in the news: only 6 FIX patients in trial, using “gutted” virus (no capacity to reproduce).

• Of 6, only 1 really took to it but he got higher ALT (liver
function measurement).

• Problems with the study: not enough data, immune response a threat and you can’t be retreated
as you will have an immune response.

• Long acting factor: many companies working on this. Everyone has different half-lives; children have shorter
ones than adults. So how long is long? New FIX drugs could be 3-5 times longer acting, meaning you might treat once every 10-14 days?

• What will price be of the longer acting drugs? What is the worth for a theoretical improvement of
life? No one yet knows.

(Our next issue of PEN in May examines all these in depth: be sure to download it!)

Dr. Neufeld was very positive about current gene therapy efforts. He made us all laugh by saying that our community has been promising us gene therapy roughly in every ten year cycles, but this time, he truly feels there is a great chance we will find it.

Just before lunch, we had panel presentations from all the pharma and specialty pharmacy reps on their patient assistance programs, delivered all above the growing din from the Bar Mitzvah next door!

These were all great presentations, and we had an attentive audience. I saw so many of my friends in hemophilia, and truly enjoyed myself. I hope you can all attend a local hemophilia event and take part in your community! We had a rap session with the moms, and one among us had an 8 month old. We all remember the feelings of when our babies were diagnosed. We felt for her. Everyone rushed to welcome her, praised her for attending, and offered email addresses and phone numbers. It never fails to amaze me how tight our community is. We are friends, and family, for life.

Great Book I Just Read

Murder in the High Himalaya: Loyalty, Tragedy, and Escape from Tibet

by Jonathan Green

This is a rare book that provides multiple levels of reading, on history, ethics, exposé, culture, politics and an unforgettable story of a young girl’s perseverance, determination and tragic legacy. I love real life adventure and survival books, especially about mountain climbing and/or history, and also books about how one person can change the world. This book has it all. On September 30, 2006 a cruel and thoughtless murder of a 17-year-old Tibetan nun (just a girl truly) by Chinese border guards triggered an avalanche of scrutiny in the press, world agencies, political leaders–and in the consciences of the Western mountain climbers on a paid guided climb who watched in horror. Kelsang Namtso was trying to escape Tibet via the mountain Cho Oyu when she was gunned down in full view of climbers, one of whom videotaped it. The tape went viral—the first time human rights violations against the Tibetans had been filmed—and the rest is history. This book tells this amazing story in gripping and often exquisite prose (much like Jon Krakauer) and provides powerful parallel stories of Kelsang and the mountain climbers, which later intersect dramatically and make history (much like author Erik Larsen). You will be amazed at the courage of this 17-year-old, and at the response by those who witnessed her death. Green’s compelling narrative will teach you much about Tibet, how it has suffered under Chinese rule, and how the West has looked away until one lone video clip, still available on YouTube, shamed us into action. Green raises excellent questions that beg an inward look at our own souls, and portrays Tibetan lives without freedom that make us instantly cherish our own freedom. A must read. Four out of five stars.