Replies to post #87189 on Biotech Values

[DewDiligence]

(NVS) Amid the impressive results of various CML studies presented
at the just completed ASH conference, I thought I’d take the opportunity
to revisit this Gleevec article from almost nine years ago.

The science behind Gleevec is well known, but who in 2001 seriously
expected Gleevec to become one of the largest-selling cancer drugs of
all time? Perhaps Dan Vasella did—about ¾ of the way into this article
is a passage, included almost as an afterthought, where Vasella warned
of the dangers of killing a promising drug too early.

http://www.nytimes.com/2001/05/08/science/powerful-anti-cancer-drug-emerges-from-basic-biology.html

›Powerful Anti-Cancer Drug Emerges from Basic Biology

May 8, 2001
By NICHOLAS WADE

A new drug that homes in on cancer cells has achieved striking preliminary results in treating a kind of leukemia and may also be effective against a rare stomach tumor.

Physicians are excited about the drug because its design is based on a deep understanding of how cancer cells work, and it could be the first of a new class of drugs designed to hit many different types of cancer.

The drug, long known by its chemical compound number STI-571 and more recently as Gleevec, is still in clinical trials but is under fast track review by the Food and Drug Administration. A spokeswoman for Novartis, its maker, said the agency might approve the drug in a matter of weeks. [The FDA approved Gleevec on May 10, 2001, two days after this article was written and only six weeks after the NDA submission.]

If successful, Gleevec will be among the first fruits of some three decades of investment in research into the basic biology of cancer. ''This really is the first clear example of a drug that targets an intracellular signaling molecule in cancer therapy and is almost through the approval process, and the results are just remarkable,'' said Dr. Ed Harlow, a leading cancer researcher at Harvard Medical School.

For now, the drug's promise rests on its use in patients suffering from chronic myelogenous leukemia, or C.M.L., one of the four main types of leukemia. The standard treatment is either a bone marrow transplant, which carries high risk, or interferon, a drug with several severe side effects. STI-571 has seized the interest of patients' groups and hematologists because within a few weeks of treatment some 90 percent of patients see their white blood cell counts revert to normal with only mild side effects, if any.

STI-571 has not yet passed the acid test of a cancer drug: proof that it makes patients live longer. [The initial FDA approval was based on the response rate in single-arm studies in the SoC-refractory setting; in 2007, the FDA label for Gleevec was updated to show a statsig OS benefit relative to the prior SoC consisting of interferon alpha plus cytarabine (a chemo drug dating to the 1960’s) in the first-line setting.] Nor do scientists know if patients may develop resistance to the drug's benefits. ''There is no direct evidence that STI-571 prolongs life. Important clinical problems could still emerge,'' was the stern caution of an otherwise positive editorial in The New England Journal of Medicine last month.

But clinical tests only began in June 1998, and the median survival time of C.M.L. patients is about six years. And the drug's success so far has been hard to ignore. In one trial reported in the [NEJM], 98 percent of patients in the early stages of the leukemia had their blood cell counts fall back to normal levels and in 13 percent no trace of cancerous cells remained; in another trial, with patients in the terminal phase of the disease, 11 percent saw blood counts return to normal.

The drug inspires special confidence among researchers because they understand with considerable precision what it is doing.

Unlike most cancers, which appear at a stage when the tumor has accumulated many different genetic defects, C.M.L. starts with a single event, although its cause is unknown: the swap of sections of DNA between two chromosomes. Two physicians noticed in 1960 that almost all C.M.L. patients possessed an oddity in their 22nd pair of chromosomes; one member was missing a short segment. The truncated copy was named the Philadelphia chromosome.

Some 25 years later, Dr. David Baltimore, now president of Caltech, and Dr. Owen Witte, now at the University of California, Los Angeles, began to understand why the swap is so dangerous. The break point occurs in the middle of two genes, one known as bcr on Chromosome 22 and another known as abl on Chromosome 9. The abl gene makes a protein that is part of the cell's internal communications system, but in the Philadelphia chromosome rearrangement the gene loses a vital section -- the piece that enables the signaling protein to shut itself off. The incessant signaling of the defective abl protein is presumably what causes the leukemia patients' white blood cells to keep dividing.

The cell's signaling system rests on an exchange of small chemicals known as phosphate groups; the abl protein rips a phosphate group off of a ubiquitous cell chemical called ATP and sticks it onto the next protein in the signaling chain. To do so, it first traps a molecule of ATP in a special cleft. STI-571 is a chemical carefully tailored to slot into the abl protein's ATP cleft and jam it.

Development of the drug began in the laboratories of Ciba-Geigy, the Swiss pharmaceutical company that merged in 1996 with Sandoz to form Novartis. In 1985, Dr. Alex Matter, head of the oncology research laboratory, started a project to exploit the new discoveries molecular biologists were making about cancer-causing genes and signal transmission inside the cell. Dr. Matter enlisted Dr. Nicholas Lydon to develop inhibitors for protein kinases, a group of about 100 different signaling proteins that includes the abl protein.

Dr. Lydon, who is now a vice president of Amgen, worked with a team that included Dr. Jürg Zimmermann, a chemist who synthesized many different chemicals, and Dr. Elisabeth Buchdunger, who tested them in cells. The project engendered much skepticism because it was not at all obvious that any chemical could be found that would inhibit a specific protein kinase without shutting down them all and wreaking havoc in the body's cells.

Dr. Lydon's program focused on a signaling protein known as the PDGF receptor, which is active in a wide variety of tumors. His team produced several chemicals that inhibited the receptor, including one designated STI-571.

Quite separately, Dr. Brian J. Druker, an oncologist interested in protein kinases, decided that a possible treatment for C.M.L. might be to inhibit the abnormal abl protein formed in the Philadelphia chromosome rearrangement. Having met Dr. Lydon before, he called to ask if Ciba-Geigy had any chemicals for him test out in leukemia cells grown in the laboratory.

Dr. Lydon sent him several candidate substances, including STI-571. Dr. Druker, who works at the Oregon Health Sciences University in Portland, tested the chemicals on cells grown in the laboratory and soon found that STI-571 inhibited cancerous white blood cells but seemed harmless to healthy human cells.

Despite this finding, further progress was far from certain. C.M.L. strikes about 4,500 people a year in the United States and a similar number in Europe. This is far too small a patient population to interest a pharmaceutical company [so they thought], which must recapture the multimillion-dollar investment required to develop a new drug. ''There were some days between 1993 and 1998 when I wasn't sure if this would make it out of the lab and into the clinic,'' Dr. Druker said.

His findings prompted a debate within Novartis between those who wanted to push ahead with STI-571 and others who argued that the investment could be spent to greater good on more common diseases.

Novartis decided to produce at least the few pounds of STI-571 needed for an initial trial, and Dr. Druker began recruiting patients in June 1998. By December 1999, in a Phase 1 trial intended merely to find a safe dose, he reported that 23 of 24 patients on a high dose had gone into complete remission within a month, as judged by the return of white blood cell count to normal levels.

Within a few months the news of STI-571 began to spread among C.M.L. support groups on the Internet. Patients clamored to be enrolled, and Dr. Druker pressed Novartis for more of the drug. But the company was in a bind. Most candidate drugs fail in the testing process, however promising the initial results. To scale up so early from manual methods of synthesis to an industrial scale process would be an enormous risk.

At this point a novel factor entered the company's usual decision making: organized pressure from patients. ''What really convinced Novartis was pressure from patients who could see this was a wonder drug,'' said Dr. Lydon, who left the company 1997 to form his own company.

One of those patients was Suzan McNamara of Montreal. The interferon she was on made her miserable, causing hair loss, depression and insomnia. Ms. McNamara called Dr. Druker, who said he had no drug to give her. Recalling a Web site that helped generate petitions for causes like favorite television programs, Ms. McNamara, with the help of a physician friend, drafted a petition to Novartis.

''We were hoping to get 200 names, and in two months before you knew it we had 2,000,'' she said. ''So we found the big honcho's name in Switzerland. We all put in our two cents and typed up the letter, saying there were people dying because they weren't getting the drug in time.''

The chief executive of Novartis, Dr. Daniel Vasella, said he had been impressed with messages he received from the patients. ''There was a big debate internally because we didn't have product,'' Dr. Vasella said of the shortages of STI-571. ''That was when I had the first communication with patients, and that's when I very much pushed for our people to make it. We needed to go from kilograms to tons. At the end of the day you are talking about something that can make people live or die.''

Within a month of sending her petition, Ms. McNamara received a phone call from Dr. Druker. ''It was on my birthday,'' she said. ''He said: 'I heard your petition has done lots of good. I think it really pushed them.' '' The company itself sent her a letter saying it planned to speed up production.

''I started in the trial on Jan. 1, 2000, and I'm in complete remission,'' she said. ''It's a fairy tale story.''

Dr. Vasella said that one of his reasons for advancing STI-571 into full-scale production, despite the very early stage of its progress and the small population of patients, was a feeling that its applications would grow. As project manager for the Sandoz drug Sandostatin, he had found that that drug turned out to have more uses than initially predicted. ''So you add knowledge and insights, and I think to block something too early is a mistake,'' he said.

Although STI-571 homes in on the abl signaling protein, it has also been found to hit two other protein kinases. One, called the c-kit receptor, is active in a cancer called gastrointestinal stromal tumor. The only treatment for the tumor is surgery, and cases that cannot be operated on are invariably fatal. The case of a single patient given STI-571 was reported last month in The New England Journal of Medicine; though she was ridden with tumors, all the tumors responded to the drug and the patient was clinically well. Results of a trial in a group of patients are to be reported at a meeting later this month of the American Society for Clinical Oncology.

Unfortunately for Novartis, the patient population for gastrointestinal stromal tumor is about 2,000 a year in the United States, even smaller than that for C.M.L. But STI-571 inhibits a third protein kinase, the PDGF receptor that was the initial target of the drug development program and is active in many common cancers. Trials of STI-571 for glioblastoma, a kind of brain tumor, were started in December 2000 under the auspices of the National Cancer Institute.

Both Dr. Druker and Dr. Lydon believe STI-571, despite its stand-alone success with C.M.L., is likely to prove most useful in combination with other drugs. Physicians are likely to start testing such combinations if STI-571 is approved.

The drug's success is also likely to stimulate efforts to design inhibitors of the signaling molecules that malfunction in other kinds of cancer. STI-571 ''is something that emerged from 40 years of hard labor and is a validation that the approach will work if the science is right,'' said Dr. David Parkinson, the Novartis official who oversees worldwide clinical trials of the drug.

''We can use the same approaches to go at other human malignancies,'' he added. As of January 2000, 10 pharmaceutical companies had mounted 16 different programs to develop signal transduction inhibitors, as the STI-571 class of drugs is known.

Novartis is now supplying the drug, free of charge, to 7,500 patients around the world. When it is approved by each country's regulatory authority, the drug will then be sold. ''We will have to charge a high price for the drug because of the small patient population,'' Dr. Vasella said, but the company would support an expanded access program in which people who could not afford the full price would receive the drug for free or a means-tested discount.

Last week, the Harvard Medical School gave a scientific prize, the Alpert Foundation award, to five people who contributed to the creation of STI-571. Besides Dr. Lydon and Dr. Druker, the recipients were Dr. Lydon's laboratory chief, Dr. Matter, and two of the researchers who unraveled the molecular cause of C.M.L., Dr. Baltimore and Dr. Witte.‹

[DewDiligence]

NVS’ Tasigna receives FDA priority review in first-line CML:

http://finance.yahoo.com/news/Novartis-Drug-TasignaR-prnews-1439979667.html?x=0&.v=1

Tasigna is already approved in all major jurisdictions for second-line CML following Gleevec, but the first-line setting (along with non-CML indications) is where the big money is. Worldwide, Gleevec outsells Tasigna and Sprycel combined by about 6:1 ($4.3B vs [$260M+$480M] annualized 4Q09 run rates).

[DewDiligence]

Tasigna Bests Gleevec at 18 Months in 1st-line CML

[The 12-month data from this study, which were reported at ASH in December (#msg-44330980), were the basis for the NDA submission in Feb 2010 to expand the Tasigna label to the first-line setting (#msg-46819994). The presentation at ASCO described here consists of 18-month data from the same study. The primary endpoint was major molecular response (MMR), defined as a >=3-log reduction in Bcr-Abl relative to an industry-standard value for untreated patients. Tasigna is battling BMY’s Sprycel for the honor of inheriting the Gleevec mantle in CML; a head-to-head study will be presented this weekend.]

http://finance.yahoo.com/news/New-Data-at-ASCO-Show-prnews-1782193640.html?x=0&.v=1

›New Data at ASCO Show Novartis Drug Tasigna® Surpasses Gleevec® for Newly Diagnosed CML Patients

• 18-month median follow-up from the first head-to-head comparison of these two oral therapies to be presented Monday, June 7 at ASCO

• Three times more patients achieved undetectable disease at the molecular level with Tasigna than with Gleevec

• In this study, Tasigna produced significantly deeper molecular responses and reduced progression to advanced disease, resulting in fewer deaths due to CML

• Tasigna registration data further confirmed by this new data; filing received FDA priority review and also submitted in EU, Switzerland and Japan

Friday June 4, 2010, 1:23 am EDT

EAST HANOVER, N.J., June 4 /PRNewswire/ -- Novartis announced today 18-month results (median follow-up) showing that Tasigna® (nilotinib) capsules significantly surpass the efficacy of Gleevec® (imatinib mesylate) tablets* in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

This 18-month median follow-up is from the first head-to-head comparison of these two oral therapies as initial treatment for this life-threatening blood cancer and will be presented on June 7 at the 46th American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

Tasigna produced significantly deeper levels of molecular response than Gleevec in front-line Ph+ CML and reduced progression to accelerated phase and blast crisis, resulting in fewer deaths due to CML. Notably, three times more patients achieved undetectable disease at the molecular level with Tasigna than with Gleevec. Further, Tasigna surpassed Gleevec in other key measures of treatment efficacy.

"Tasigna demonstrates that by more selectively inhibiting BCR-ABL, the key driver of Ph+ CML, we can reduce progression to advanced disease even further than with the current gold standard Gleevec," said Richard Larson, MD, ENESTnd study investigator and Director of the Hematologic Malignancies Program at the University of Chicago. "The efficacy and safety findings achieved by Tasigna in this study provide patients and physicians with an important potential new treatment option."

In February 2010, the US Food & Drug Administration (FDA) granted Tasigna priority review status for newly diagnosed Ph+ CML patients. Regulatory submissions have been filed in the European Union (EU), Switzerland and Japan. The new ENESTnd data to be presented at ASCO will further confirm the findings in those filings, all of which were based on 13.8-month median follow-up data from the study.

Study details

The clinical trial, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd), is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients.

ENESTnd is being conducted at 217 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 300 mg twice daily (n = 282), Tasigna 400 mg twice daily (n = 281) or Gleevec 400 mg once daily (n = 283). The primary endpoint was major molecular response (MMR) at 12 months; a secondary endpoint was complete cytogenetic response (CCyR) by 12 months. Planned follow-up is for five years. Patients on the Gleevec treatment arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to Tasigna via a protocol extension. The data to be presented at ASCO is the 18-month median follow-up.

MMR was defined in the study as reduction in the level of the abnormal BCR-ABL gene to less than or equal to 0.1% of the pretreatment level based on an internationally agreed standard. Notably, three times more patients in the ENESTnd study achieved undetectable disease at the molecular level (BCR-ABL levels at 4.5-log reduction) with Tasigna than with Gleevec, at the 18-month median follow-up. CCyR indicates that no CML cells containing the diagnostic Philadelphia chromosome can be seen in a sample of bone marrow taken from the patient.

Results showed that fewer patients progressed to accelerated phase or blast crisis on Tasigna at 300 mg twice daily (n = 2) and 400 mg twice daily (n = 1) versus Gleevec at 400 mg once daily (n = 12) with 18 months of median follow-up, demonstrating an improvement in disease control. The data also showed fewer deaths due to CML on Tasigna at 300 mg twice daily (n = 2) and 400 mg twice daily (n = 1) versus Gleevec at 400 mg once daily (n = 8). Rate of MMR and CCyR remain superior for Tasigna versus Gleevec at the 18-month median follow-up.

All patients had a minimum of 16 months of treatment or discontinued early; the median follow-up was 18 months. Overall, 80%, 81% and 75% of patients remained in the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec 400 mg once daily, respectively.

Both Tasigna and Gleevec were well tolerated overall. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for Tasigna 300 mg twice daily, 11% for Tasigna 400 mg twice daily, and 9% for Gleevec 400 mg once daily. Fewer patients taking Tasigna discontinued due to adverse events compared to Gleevec. No patients in the study had prolongation of QT interval >500 milliseconds. No sudden deaths occurred in any of the treatment arms.

About Ph+ CML

CML is a disease in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces a protein called BCR-ABL. BCR-ABL causes malignant white blood cells to proliferate. Worldwide, CML is responsible for approximately 10% to 15% of all adult cases of leukemia, with an incidence of one to two cases per 100,000 people per year.

About Tasigna

Tasigna has been approved in more than 80 countries for the treatment of chronic phase (CP) and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec. The effectiveness of Tasigna for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.‹

[DewDiligence]

FDA approves NVS’ Tasigna in first-line CML:

http://finance.yahoo.com/news/FDA-Approves-Tasigna-for-prnews-1908800772.html?x=0&.v=1

Tasigna has worldwide annualized sales of $300M (#msg-49185209) based almost entirely on use in the second-line (Gleevec-refractory) setting. With the newly expanded label, Tasigna’s sales will increase greatly notwithstanding the fact that Tasigna will eventually have to split the first-line CML indication with GSK’s Sprycel and other agents. This can be ascertained from simple arithmetic: Gleevec, the NVS drug that Tasigna bested with ease in a head-to-head study (#msg-50898190), has annual sales of $4B (#msg-49185209).